RU2734501C2 - Selective estrogen receptor inhibitors and use thereof - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention refers to compounds of formulas (I) and (II) and their pharmaceutically acceptable salts possessing properties of selective estrogen receptor inhibitors. In formula (I) A is -CH= or -N= depending on valence; W is -NH- or -O-; a is equal to 1; n is 1, 2, 3 or 4; each R¹ independently represents hydrogen, F, Cl, unsubstituted C_1-6 alkyl, -CF₃, -OR^A or -CN; R² denotes hydrogen, unsubstituted C_1-6 alkyl or CF₃; R³ denotes hydrogen, halogen or unsubstituted C_1-6 alkyl; R⁴ is hydrogen, halogen or unsubstituted C_1-6 alkyl; R⁵ denotes chlorine; R⁶ denotes fluorine or chlorine; R⁷ is -CH₂F; R^A is hydrogen or unsubstituted C_1-6 alkyl. In formula (II) A is -CH= or -N= depending on valence; W is -NH-, -O- or -S-; a is equal to 1; each R¹ independently represents hydrogen, F, Cl, -CF₃, unsubstituted C_1-6 alkyl, -OR^A or -CN; R² denotes hydrogen, unsubstituted C_1-6 alkyl or -CF₃; R³ denotes hydrogen, F or unsubstituted C_1-6 alkyl; R⁴ is hydrogen, F or unsubstituted C_1-6 alkyl, or R³ and R⁴ taken together with intermediate atoms form unsubstituted cyclopropyl; R⁸ represents hydrogen, halogen or methyl; R^A1 represents unsubstituted C_1-6 alkyl, chloro or fluoro; R^A2 is unsubstituted C_1-6 alkyl, chlorine or fluorine; wherein: (i) R^A1 or R^A2 is chlorine or (ii) both R^A1 and R^A2 are chlorine; R^A is hydrogen or unsubstituted C_1-6 alkyl. Invention also relates to pharmaceutical composition, containing an effective amount of compounds of formulas (I) or (II) or their pharmaceutically acceptable salts and a pharmaceutically acceptable excipient. Described also is a method of treating a proliferative disease associated with estrogen receptor activity, comprising administering to a subject in need of treatment, effective amount of the pharmaceutical composition of the invention.

EFFECT: presented are selective estrogen receptor inhibitors and their application.

18 cl, 3 dwg, 8 tbl, 14 ex

Description

Cross-reference to related claims

[0001] This application claims priority under 35 USC §119 (e) pursuant to US Provisional Application 62/291921, filed February 5, 2016, which is incorporated herein by reference in its entirety.

State of the art

[0002] Breast cancer is the most common cause of death in women worldwide. Most cases of breast cancer (approximately 80%) are associated with a signaling pathway that regulates cell growth mediated by estrogen receptors (ER). Therefore, targeted therapy of ER or their signaling pathway remains a key direction in the development of a drug for the treatment of breast cancer. Estrogen receptors (including ERα and ERβ) are a group of receptors that are activated by estrogen hormone (17β-estradiol). Current therapy for ER-positive (ER +) breast cancer includes agents that inhibit ER activity by directly binding to the ligand-binding domain of the receptor (e.g. tamoxifen), block estrogen synthesis (e.g., an aromatase inhibitor such as anastrozole and letrozole), or induce degradation ER (for example, fulvestrant).

[0003] Drugs that inhibit estrogen receptors or block the formation of estrogen are commonly used to treat ER-positive breast cancer and other hormone-dependent cancers. However, drug resistance remains a problem for the treatment of breast cancer, especially for the treatment of advanced cancer. Selective estrogen receptor inhibitors (SSRIs) are a class of small molecules that bind to the estrogen receptor, resulting in degradation of the estrogen receptor. Research has shown that SEEDs are particularly useful for treating cancers that are resistant to other drugs such as tamoxifen and / or aromatase inhibitors (McDonnell et al., J. Med. Chem. 2015, 58, 4883-4887). Fulvestrant is an SRED approved for the treatment of ER-positive breast cancer. However, fulvestrant is rapidly metabolized, in addition, it is administered by intramuscular injection once a month, which limits the effective degradation of ER (degradation of ER in clinical samples is approximately 50%) compared to the complete degradation of ER observed in an in vitro study. Recently, ER mutations have been found in biopsy samples from breast cancer patients who have developed resistance to treatment with an aromatase inhibitor. These mutations are most often found in amino acids 537 and 538 in the ligand-binding domain of the ER. Interestingly, these mutated ERs are still associated and inhibited by both tamoxifen and fulvestrant to some extent (Li et al., 2013 Cell Reports 4, 1116-1130; Toy et al., 2013, 45, 1439-1445; Robinson et al., Nature Genetics 2013, 45, 1446-1451). It has also been shown that fulvestrant can effectively induce degradation of the mutated Try537Ser ER protein. As a result, a compound targeting ER degradation, like fulvestrant, can effectively degrade the mutated ER protein, and is also useful for treating breast cancer patients who have developed resistance to an aromatase inhibitor. Therefore, it is very important to develop new non-steroidal SREDs for the treatment of breast cancer and other diseases associated with ER.

The essence of the invention

[0004] The present invention provides compounds, such as those of Formula (I) and Formula (II), which are selective estrogen receptor inhibitors (SEERs). The compounds described herein are useful for the treatment of breast cancer, especially ER-positive breast cancer, as well as ER-related diseases. Also provided are pharmaceutical compositions, kits, methods, and uses for any of the compounds described herein.

[0005] In one aspect, the present invention provides compounds of Formula (I):

or pharmaceutically acceptable salts, wherein A is -CR ^A = or -N = depending on the valency; W represents -NH-, -O- or -S-; a is 1, 2, or 3; and n is 1, 2, 3, or 4. In addition,

each R ^{1 is} independently hydrogen, halogen, substituted or unsubstituted alkyl, —OR ^A, or —CN;

R ² is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl;

R ³ is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, —OR ^A or —N (R ^B ) ₂ ;

R ⁴ is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, —OR ^A or —N (R ^B ) ₂ ;

R ⁵ is hydrogen, halogen, substituted or unsubstituted alkyl;

R ⁶ is hydrogen, substituted or unsubstituted alkyl;

R ⁷ is hydrogen, halogen, substituted or unsubstituted alkyl, —OR ^A, or —N (R ^B ) ₂ ;

R ^A is hydrogen or a substituted or unsubstituted alkyl or oxygen protecting group; and

R ^B is hydrogen or a substituted or unsubstituted alkyl, a nitrogen protecting group, or optionally two R ^B taken together with intermediate atoms form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

[0006] In some embodiments, the compound of Formula (I) is a compound of the formula:

или фармацевтически приемлемую соль, причем R¹, R², R³, R⁴, R⁵, R⁶, R⁷, A, W, а и n как описаны в данном документе.

or a pharmaceutically acceptable salt, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , A, W, a and n are as described herein.

[0007] Examples of compounds of Formula (I)

[0008] include, but are not limited to:

или фармацевтически приемлемые соли.

or pharmaceutically acceptable salts.

[0009] In another aspect, the present invention provides compounds of Formula (II):

or pharmaceutically acceptable salts, wherein A is -CR ^A = or -N = depending on the valency; W represents -NH-, -O- or -S-; and a is 1, 2, or 3. In addition,

each R ^{1 is} independently hydrogen, halogen, substituted or unsubstituted alkyl, —OR ^A, or —CN;

R ² is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl;

R ³ is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, —OR ^A or —N (R ^B ) ₂ ;

R ⁴ is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, —OR ^A or —N (R ^B ) ₂ or R ³ and R ⁴ taken together with intermediate atoms form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

R ⁸ is hydrogen, halogen, or substituted or unsubstituted methyl (eg methyl);

R ^A1 represents substituted or unsubstituted alkyl, chlorine or fluorine; and

R ^A2 is substituted or unsubstituted alkyl, chlorine or fluoro, wherein: (i) R ^A1 or R ^A2 is chlorine; or (ii) one of R ^A1 and R ^A2 is fluoro and the other of R ^A1 and R ^{A2 is} selected from the group consisting of unsubstituted alkyl, chloro and fluoro

R ^A is hydrogen or a substituted or unsubstituted alkyl or oxygen protecting group; and

R ^B is hydrogen or substituted or unsubstituted alkyl, a nitrogen protecting group, or optionally two R ^B taken together with intermediate atoms form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

[0010] In some embodiments, the compound of Formula (II) is a compound of the formula:

or a pharmaceutically acceptable salt, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁸ , R ^A1 , R ^A2 , A, W and a are as described herein.

[0011] In some embodiments, at least one of R ^A1 and R ^A2 in Formula (II) may be chlorine. In some embodiments, both R ^A1 and R ^A2 in Formula (II) may be chlorine. Examples of compounds of Formula (II) include, but are not limited to:

and their pharmaceutically acceptable salts.

[0012] In some embodiments, R ^A1 in Formula (II) may be fluorine and R ^A2 may be methyl, for example, compound 41 below:

[0013] In some embodiments, when both R ^A1 and R ^A2 in Formula (II) are fluoro, the compound also satisfies at least one of the following conditions:

W represents O or S;

at least one of R1 is not hydrogen;

R ^{2 is} not hydrogen or methyl;

A is —N or —CR ^A , wherein R ^A is a substituted or unsubstituted alkyl or oxygen protecting group;

R ³ and R ⁴ taken together with intermediate atoms form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; and

at least two of R ³ , R ⁴ and R ^{8 are} each independently halogen.

[0014] Examples of these compounds of Formula (II) include, but are not limited to:

а также фармацевтически приемлемые соли.

as well as pharmaceutically acceptable salts.

[0015] In another aspect, the present invention provides a pharmaceutical composition comprising one or more of the compounds described herein, as well as a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions described herein comprise an effective amount of the SIEV compound described herein. An effective amount as used herein is a therapeutically effective amount or a prophylactically effective amount.

[0016] In yet another aspect, the present invention provides methods for treating a proliferative disease (eg, ER-positive breast cancer, which may be wild-type or with ER mutations), the method comprising administering to a subject in need of treatment an effective amount of any of the pharmaceutical compositions described herein.

[0017] In some embodiments, the target proliferative disease can be cancer, including but not limited to ER-positive breast cancer or cancers caused by wild-type ER or ER with mutations.

[0018] In some embodiments, the subject of treatment is a mammal (eg, human or non-human mammal).

[0019] Another aspect of the present invention relates to a kit comprising a container with a compound or a pharmaceutical composition thereof as described herein. The kits described herein can include a single dose or multiple doses of a compound or pharmaceutical composition. The kits can be used in the method according to the invention. In certain embodiments, the kit further comprises instructions for use of the compound or pharmaceutical composition.

[0020] In yet another aspect, the present invention provides compounds and pharmaceutical compositions described herein for use in the treatment of a proliferative disease such as cancer as described herein and / or for the preparation of a medicament for use in the treatment of a target disease ...

[0021] Details of one or more embodiments of the invention are set forth in the description below. Other embodiments, objects and advantages of the present invention will be apparent from the following detailed description, examples and claims.

Definitions

[0022] In more detail, the definitions of specific functional groups and chemical terms are described below. The chemical elements are listed in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, endpaper, and definitions of specific functional groups are provided herein. In addition, general principles of organic chemistry as well as specific functional moieties and reactivity are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 ^{th Edition, John Wiley & Sons,} Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis , 3 ^{rd Edition, Cambridge University Press, Cambridge} , 1987. The invention is not limited in any way a list of examples of the substituents described herein.

[0023] The compounds described herein can contain one or more asymmetric centers and, thus, can be in various isomeric forms, for example, in the form of enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of a single enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; preferred isomers can also be obtained by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33: 2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. Of Notre Dame Press, Notre Dame, IN 1972). In addition, the invention includes the compounds described herein as separate isomers substantially free of other isomers and, alternatively, as mixtures of different isomers.

[0024] The range of values specified herein includes each value and sub-range within the specified range. For example, "C _1-6 " includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _{1- 2} , C _2-6 , C _2-5 , C _2-4 , C _2-3 , C _3-6 , C _3-5 , C _3-4 , C _4-6 , C _4-5 and C _{5- 6} .

[0025] The term "aliphatic" includes both saturated and unsaturated straight chain (ie, unbranched), branched, acyclic, cyclic or polycyclic aliphatic hydrocarbons, optionally substituted with one or more functional groups. As understood by a person skilled in the art, the term "aliphatic" as used herein includes, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Thus, the term "alkyl" includes straight, branched and cyclic alkyl groups. A similar definition applies to other general terms such as "alkenyl", "alkynyl" and the like. In addition, the terms "alkyl", "alkenyl", "alkynyl" and the like include both substituted and unsubstituted groups. In some embodiments, the term "lower alkyl" is used to refer to alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) containing 1-6 carbon atoms.

[0026] In some embodiments, the alkyl, alkenyl, and alkynyl groups used herein contain 1-20 aliphatic carbon atoms. In some other embodiments, the alkyl, alkenyl, and alkynyl groups used herein contain 1-10 aliphatic carbon atoms. In some other embodiments, the alkyl, alkenyl, and alkynyl groups used herein contain 1-8 aliphatic carbon atoms. In other embodiments, the alkyl, alkenyl, and alkynyl groups used herein contain 1-6 aliphatic carbon atoms. In some other embodiments, the alkyl, alkenyl, and alkynyl groups used herein contain 1-4 aliphatic carbon atoms. Thus, examples of aliphatic groups include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, —CH ₂ -cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl , cyclobutyl, —CH ₂ -cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, —CH ₂ -cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, —CH ₂ -cyclohexyl moieties and the like , which can also have one or more substituents. Examples of alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.

[0027] The term "alkyl" refers to the radical of an unbranched or branched saturated hydrocarbon group containing from 1 to 10 carbon atoms ("C _1-10 alkyl"). In some embodiments, the alkyl group contains from 1 to 9 carbon atoms ("C _1-9 alkyl"). In some embodiments, the alkyl group contains from 1 to 8 carbon atoms (“C _1-8 alkyl”). In some embodiments, the alkyl group contains from 1 to 7 carbon atoms ("C _1-7 alkyl"). In some embodiments, the alkyl group contains from 1 to 6 carbon atoms (“C _1-6 alkyl”). In some embodiments, the alkyl group contains from 1 to 5 carbon atoms ("C _1-5 alkyl"). In some embodiments, the alkyl group contains 1 to 4 carbon atoms ("C _1-4 alkyl"). In some embodiments, the alkyl group contains 1 to 3 carbon atoms (“C _1-3 alkyl”). In some embodiments, the alkyl group contains 1 to 2 carbon atoms ("C _1-2 alkyl"). In some embodiments, the alkyl group contains 1 carbon atom ("C ₁ alkyl"). In some embodiments, the alkyl group contains from 2 to 6 carbon atoms ("C _2-6 alkyl"). Examples of C _1-6 alkyl groups include methyl (C ₁ ), ethyl (C ₂ ), propyl (C ₃ ), (eg n-propyl, isopropyl), butyl (C ₄ ) (eg n-butyl, tert- butyl, sec-butyl, isobutyl), pentyl (C ₅ ) (e.g. n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl) and hexyl (C ₆ ) (e.g. n -hexyl). Additional examples of alkyl groups include n-heptyl (C ₇ ), n-octyl (C ₈ ), and the like. Unless otherwise indicated, each alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (eg, halogen such as F). In some embodiments, the alkyl group is unsubstituted C _1-10 alkyl (eg, unsubstituted C _1-6 alkyl, eg —CH ₃ ). In some embodiments, the alkyl group is substituted C _1-10 alkyl (eg, substituted C _1-6 alkyl, eg —CF ₃ ).

), может представлять собой (E)- или (Z)-двойную связь.[0028] "Alkenyl" refers to a radical of a straight or branched hydrocarbon group that contains from 2 to 20 carbon atoms, one or more carbon-carbon double bonds and does not contain triple bonds ("C _2-20 alkenyl"). In some embodiments, the alkenyl group contains 2 to 10 carbon atoms (“C _2-10 alkenyl”). In some embodiments, the alkenyl group contains 2 to 9 carbon atoms (“C _2-9 alkenyl”). In some embodiments, the alkenyl group contains 2 to 8 carbon atoms (“C _2-8 alkenyl”). In some embodiments, the alkenyl group contains 2 to 7 carbon atoms ("C _2-7 alkenyl"). In some embodiments, the alkenyl group contains 2 to 6 carbon atoms ("C _2-6 alkenyl"). In some embodiments, the alkenyl group contains 2 to 5 carbon atoms ("C _2-5 alkenyl"). In some embodiments, the alkenyl group contains 2 to 4 carbon atoms ("C _2-4 alkenyl"). In some embodiments, the alkenyl group contains 2 to 3 carbon atoms (“C _2-3 alkenyl”). In some embodiments, the alkenyl group contains 2 carbon atoms ("C ₂ alkenyl"). One or more carbon-carbon double bonds can be internal (eg, in 2-butenyl) or terminal (eg, in 1-butenyl). Examples of C _2-4 alkenyl groups include ethenyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ) etc. Examples of C _2-6 alkenyl groups include the above C _2-4 alkenyl groups as well as pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ) and the like. Additional examples of alkenyl include heptenyl (C ₇ ), octenyl (C ₈ ), octatrienyl (C ₈ ), and the like. Unless otherwise indicated, each alkenyl group is independently optionally substituted, that is, unsubstituted ("unsubstituted alkenyl") or substituted ("substituted alkenyl") with one or more substituents. In some embodiments, the alkenyl group is unsubstituted C _2-10 alkenyl. In some embodiments, the alkenyl group is substituted C _2-10 alkenyl. In the alkenyl group, the C = C double bond, the stereochemistry of which has not been determined (for example, -CH = CHCH ₃

), can be an (E) - or (Z) -double bond.

[0029] "Alkynyl" refers to a radical of an unbranched or branched hydrocarbon group containing from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds (“C _2-20 alkynyl”). In some embodiments, the alkynyl group contains 2 to 10 carbon atoms (“C _2-10 alkynyl”). In some embodiments, an alkynyl group contains from 2 to 9 carbon atoms (“C _2-9 alkynyl”). In some embodiments, an alkynyl group contains from 2 to 8 carbon atoms (“C _2-8 alkynyl”). In some embodiments, an alkynyl group contains 2 to 7 carbon atoms ("C _2-7 alkynyl"). In some embodiments, an alkynyl group contains 2 to 6 carbon atoms ("C _2-6 alkynyl"). In some embodiments, an alkynyl group contains from 2 to 5 carbon atoms (“C _2-5 alkynyl”). In some embodiments, the alkynyl group contains 2 to 4 carbon atoms (“C _2-4 alkynyl”). In some embodiments, the alkynyl group contains 2 to 3 carbon atoms ("C _2-3 alkynyl"). In some embodiments, the alkynyl group contains 2 carbon atoms ("C ₂ alkynyl"). One or more carbon-carbon triple bonds can be internal (eg, in 2-butynyl) or terminal (eg, in 1-butynyl). Examples of C _2-4 alkynyl groups include, without limitation, ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), 2-butynyl (C ₄ ), and the like. Examples of C _2-6 alkenyl groups include the above C _2-4 alkynyl groups as well as pentynyl (C ₅ ), hexynyl (C ₆ ) and the like. Additional examples of alkynyl include heptynyl (C ₇ ), octynyl (C ₈ ), and the like. Unless otherwise indicated, each alkynyl group is independently optionally substituted, that is, unsubstituted ("unsubstituted alkynyl") or substituted ("substituted alkynyl") with one or more substituents. In some embodiments, the alkynyl group is unsubstituted C _2-10 alkynyl. In some embodiments, the alkynyl group is substituted C _2-10 alkynyl.

[0030] The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group containing from 3 to 10 ring carbon atoms ("C _3-10 carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C _3-8 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C _3-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C _3-6 carbocyclyl"). In some embodiments, the carbocyclyl group contains 5 to 10 ring carbon atoms ("C _5-10 carbocyclyl"). Examples of C _3-6 carbocyclyl groups include, without limitation, cyclopropyl (C ₃ ), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl (C ₅ ), cyclopentenyl (C ₅ ), cyclohexyl ( C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ) and the like. Examples of C _3-8 carbocyclyl groups include, without limitation, the above C _3-6 carbocyclyl groups as well as cycloheptyl (C ₇ ), cycloheptenyl (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), cyclooctyl (C ₈ ), cyclooctenyl (C ₈ ), bicyclo [2.2.1] heptanyl (C ₇ ), bicyclo [2.2.2] octanyl (C ₇ ) and the like. Examples of C _3-10 carbocyclyl groups include, but are not limited to, the above C _3-8 carbocyclyl groups as well as cyclononyl (C ₉ ), cyclononenyl (C ₉ ), cyclodecyl (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro-1H -indenyl (C ₉ ), decahydronaphthalenyl (C ₁₀ ), spiro [4.5] decanyl (C ₁₀ ) and the like. As follows from the examples above, in some embodiments, the carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged or spiro-ring system such as a bicyclic system ("bicyclic carbocyclyl"), and may be saturated or partially unsaturated ... "Carbocyclyl" also includes ring systems in which a carbocyclic ring as defined above is bonded to one or more aryl or heteroaryl groups with the point of attachment on the carbocyclic ring and in such cases the number of carbon atoms refers to the number of carbon atoms in the carbocyclic ring system. Unless otherwise indicated, each carbocyclyl group is independently optionally substituted, that is, unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") with one or more substituents. In some embodiments, the carbocyclyl group is an unsubstituted C _3-10 carbocyclyl. In some embodiments, the carbocyclyl group is substituted C _3-10 carbocyclyl.

[0031] In some embodiments, “carbocyclyl” is a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms (“C _3-10 cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms (“C _3-8 cycloalkyl”). In some embodiments, the cycloalkyl group contains 3 to 6 ring carbon atoms (“C _3-6 cycloalkyl”). In some embodiments, the cycloalkyl group contains 5 to 6 ring carbon atoms ("C _5-6 cycloalkyl"). In some embodiments, the cycloalkyl group contains 5 to 10 ring carbon atoms ("C _5-10 cycloalkyl"). Examples of C _5-6 cycloalkyl groups include cyclopentyl (C ₅ ) and cyclohexyl (C ₅ ). Examples of C _3-6 cycloalkyl groups include the above C _5-6 cycloalkyl groups as well as cyclopropyl (C ₃ ) and cyclobutyl (C ₄ ). Examples of C _3-8 cycloalkyl groups include the above C _3-6 cycloalkyl groups as well as cycloheptyl (C ₇ ) and cyclooctyl (C ₈ ). Unless otherwise indicated, each cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In some embodiments, the cycloalkyl group is unsubstituted C _3-10 cycloalkyl. In some embodiments, the cycloalkyl group is substituted C _3-10 cycloalkyl.

[0032] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3-10 membered non-aromatic ring system containing ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-10 membered heterocyclyl"). In heterocyclic groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, depending on the valence. The heterocyclyl group can be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro-ring system such as a bicyclic system ("bicyclic heterocyclyl"), and can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclic ring as defined above is attached to one or more carbocyclyl groups in which the point of attachment is on a carbocyclyl or heterocyclic ring, or ring systems in which a heterocyclic ring is as defined above, attached to one or more aryl or heteroaryl groups in which the point of attachment is on the heterocyclic ring, and in such cases the number of ring members refers to the number of ring members in the heterocyclic ring system. Unless otherwise indicated, each heterocyclyl group is independently optionally substituted, that is, unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") with one or more substituents. In some embodiments, the heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl. In some embodiments, the heterocyclyl group is a substituted 3-10 membered heterocyclyl.

[0033] In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system containing ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (" 5-10 membered heterocyclyl "). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system containing ring carbon atoms and 1-4 heteroatoms, with each heteroatom independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system containing ring carbon atoms and 1-4 heteroatoms, with each heteroatom independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl contains 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl contains 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl contains one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0034] Examples of 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiiranyl. Examples of 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Examples of 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Examples of 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Examples of 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Examples of 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Examples of 7 membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanil. Examples of 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxekanyl, and thiocanil. Typical 5-membered heterocyclyl groups attached to the C ₆ aryl ring (also referred to herein as 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Typical 6-membered heterocyclyl groups attached to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0035] "Aryl" refers to a radical of a monocyclic or polycyclic (eg, bicyclic or tricyclic) 4n + 2 aromatic ring system (eg, containing 6, 10, or 14 pi-electrons in a cyclic matrix) containing 6-14 ring carbon atoms and zero heteroatoms in the aromatic ring system ("C _6-14 aryl"). In some embodiments, the aryl group contains six ring carbon atoms ("C ₆ aryl"; eg, phenyl). In some embodiments, the aryl group contains ten ring carbon atoms ("C ₁₀ aryl"; eg, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group contains 14 ring carbon atoms ("C ₁₄ aryl"; eg, anthracil). "Aryl" also includes ring systems in which the aryl ring, as defined above, is bonded to one or more carbocyclyl or heterocyclyl groups with the radical or point of attachment on the aryl ring, in such cases the number of carbon atoms refers to the number of carbon atoms in the aryl ring system. Unless otherwise indicated, each aryl group is independently optionally substituted, that is, unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents. In some embodiments, the aryl group is unsubstituted C _6-14 aryl. In some embodiments, the aryl group is substituted C _6-14 aryl.

[0036] "Aralkyl" is a subgroup of alkyl and aryl and refers to an optionally substituted alkyl group substituted with an optionally substituted aryl group. In some embodiments, the aralkyl is optionally substituted benzyl. In some embodiments, the aralkyl is benzyl. In some embodiments, the aralkyl is optionally substituted phenethyl. In some embodiments, the aralkyl is phenethyl.

[0037] "Heteroaryl" refers to the radical of a 5-10 membered monocyclic or bicyclic 4n + 2 aromatic ring system (for example, containing 6 or 10 pi-electrons in a cyclic matrix) containing ring carbon atoms and 1-4 ring heteroatoms in the system an aromatic ring, each heteroatom independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heterocyclic groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, depending on the valence. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems in which a heteroaryl ring, as defined above, is bonded to one or more carbocyclyl or heterocyclyl groups, the point of attachment being on the heteroaryl ring, in such cases the number of ring members refers to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is linked to one or more aryl groups, with the point of attachment on the aryl or heteroaryl ring, in such cases the number of ring members refers to the number of ring members in the attached (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups in which one ring does not contain a heteroatom (for example, indolyl, quinolinyl, carbazolyl, and the like), the point of attachment can be on any ring, that is, either on a ring containing a heteroatom (for example, 2-indolyl), or on a ring that does not contain a heteroatom (for example, 5-indolyl).

[0038] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system containing ring carbon atoms and 1-4 ring heteroatoms in an aromatic ring system, with each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- 10-membered heteroaryl "). In some embodiments, the heteroaryl group is a 5-8 membered non-aromatic ring system containing ring carbon atoms and 1-4 heteroatoms in an aromatic ring system, with each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl "). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system containing ring carbon atoms and 1-4 heteroatoms in an aromatic ring system, with each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl "). In some embodiments, the 5-6 membered heteroaryl contains 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl contains 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl contains 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise indicated, each heteroaryl group is independently optionally substituted, that is, unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents. In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0039] Examples of 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Examples of 5 membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Examples of 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Examples of 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Examples of 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepynyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxazadiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, benzothiotriazyl Examples of 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0040] "Heteroaralkyl" is a subgroup of alkyl and heteroaryl and refers to an optionally substituted alkyl group substituted with an optionally substituted heteroaryl group.

[0041] The term "unsaturated" or "partially unsaturated" refers to a group containing at least one double or triple bond. The term "partially unsaturated" ring systems includes rings containing multiple unsaturated moieties, but does not include aromatic groups (eg, aryl or heteroaryl groups). Similarly, "saturated" refers to a group that does not contain a double or triple bond, that is, contains only single bonds.

[0042] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups, which are divalent bridging groups, are further referred to using the suffix "-ene", for example, alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and.

[0043] The atom, fragment or group described in this document can be unsubstituted or substituted, depending on the valency, unless explicitly indicated otherwise. The term "optionally substituted" means substituted or unsubstituted.

[0044] The group is optionally substituted, unless explicitly indicated otherwise. The term "optionally substituted" means substituted or unsubstituted. In some embodiments, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl , "Substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl and "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted", before which the term "optionally" is used or not, means that at least one hydrogen present in the group (for example, a carbon or nitrogen atom) is replaced with a permissible substituent, for example, a substituent, upon which substitution is formed a stable compound, for example, a compound that does not spontaneously undergo transformation, for example, as a result of rearrangement, cyclization, elimination or other reaction. Unless otherwise indicated, a "substituted" group contains a substituent at one or more positions in the group, and when substituted at more than one position in any given structure, the substituents may be the same or different at each position. The term "substituted" is intended to include the substitution of all permissible substituents of organic compounds, all substituents described herein, to form a stable compound. The present invention includes any of these combinations to obtain a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent, as described herein, that satisfy the valence of the heteroatoms and result in a stable moiety. In some embodiments, the substituent is a carbon substituent. In some embodiments, the substituent is a nitrogen substituent. In some embodiments, the substituent is an oxygen substituent. In some embodiments, the substituent is a sulfur substituent.

Examples of substituents on the carbon atom include, but are not limited to, halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^aa , -ON (R ^bb ) ₂ , - N (R ^bb ) ₂ , -N (R ^bb ) ₃ ⁺ X ^- , -N (OR ^cc ) R ^bb , -SH, -SR ^aa , -SSR ^cc , -C (= O) R ^aa , -CO ₂ H, -CHO, -C (OR ^cc ) ₂ , -CO ₂ R ^aa , -OC (= O) R ^aa , -OCO ₂ R ^aa , -C (= O) N (R ^bb ) ₂ , -OC ( = O) N (R ^bb ) ₂ , -NR ^bb C (= O) R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C (= O) N (R ^bb ) ₂ , -C (= NR ^bb ) R ^aa , -C (= NR ^bb ) OR ^aa , -OC (= NR ^bb ) R ^aa , -OC (= NR ^bb ) OR ^aa , -C (= NR ^bb ) N (R ^bb ) ₂ , -OC (= NR ^bb ) N (R ^bb ) ₂ , -NR ^bb C (= NR ^bb ) N (R ^bb ) ₂ , -C (= O) NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , - SO ₂ N (R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S (= O) R ^aa , -OS (= O) R ^aa , -Si (R ^aa ) ₃ , -OSi (R ^aa ) ₃ -C (= S) N (R ^bb ) ₂ , -C (= O) SR ^aa , -C (= S) SR ^aa , -SC (= S) SR ^aa , -SC (= O) SR ^aa , -OC (= O) SR ^aa , -SC (= O) OR ^aa , -SC (= O) R ^aa , -P (= O) (R ^aa ) ₂ , -P (= O) (OR ^cc ) ₂ , -OP (= O) (R ^aa ) ₂ , -OP (= O) (OR ^cc ) ₂ , -P (= O) (N (R ^bb ) ₂ ) ₂ , -OP (= O) (N (R ^bb ) ₂ ) ₂ , -NR ^bb P (= O) (R ^aa ) ₂ , -NR ^bb P (= O) (OR ^cc ) ₂ , -NR ^bb P (= O) (N (R ^bb ) ₂ ) ₂ , -P (R ^cc ) ₂ , -P (OR ^cc ) ₂ , -P (R ^cc ) ₃ ⁺ X ^- , -P (OR ^cc ) ₃ ⁺ X ^- , -P (R ^cc ) ₄ , -P (OR ^cc ) ₄ , -OP (R ^cc ) ₂ , -OP (R ^cc ) ₃ ⁺ X ^- , -OP (OR ^cc ) ₂ , -OP (OR ^cc ) ₃ ⁺ X ^- , -OP (R ^cc ) ₄ , -OP (OR ^cc ) ₄ , -B (R ^aa ) ₂ , -B (OR ^cc ) ₂ , -BR ^aa (OR ^cc ), C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _{6 -14} aryl and 5-14 membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd ; where X ^- is a counterion;

or two geminal hydrogen atoms on a carbon atom are replaced by = O, = S, = NN (R ^bb ) ₂ , = NNR ^bb C (= O) R ^aa , = NNR ^bb C (= O) OR ^aa , = NNR ^bb S (= O) ₂ R ^aa , = NR ^bb or = NOR ^cc ;

each R ^{aa is} independently selected from C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl and 5 -14-membered heteroaryl, or two R ^aa groups are connected to form a 3-14-membered heterocyclyl or 5-14-membered heteroaryl ring, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently substituted with group 0, 1, 2, 3, 4 or 5 R ^dd ;

each R ^{bb is} independently selected from hydrogen, -OH, -OR ^aa , -N (R ^cc ) ₂ , -CN, -C (= O) R ^aa , -C (= O) N (R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C (= NR ^cc ) OR ^aa , -C (= NR ^cc ) N (R ^cc ) ₂ , -SO ₂ N (R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C (= S) N (R ^cc ) ₂ , -C (= O) SR ^cc , -C (= S) SR ^cc , -P (= O) (R ^aa ) ₂ , -P (= O) (OR ^cc ) ₂ , -P (= O) (N (R ^cc ) ₂ ) ₂ , C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, or two R ^bb groups are linked to form a 3-14 membered heterocyclyl or 5-14- a member heteroaryl ring, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd ; where X ^- is a counterion;

each R ^{cc is} independently selected from C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl and 5 -14-membered heteroaryl, or two R ^cc groups are connected to form a 3-14-membered heterocyclyl or 5-14-membered heteroaryl ring, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently substituted with 0 groups, 1, 2, 3, 4 or 5 R ^dd ;

each R ^{dd is} independently selected from halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^ee , -ON (R ^ff ) ₂ , -N (R ^ff ) ₂ , -N (R ^ff ) ₃ ⁺ X ^- , -N (OR ^ee ) R ^ff , -SH, -SR ^ee , -SSR ^ee , -C (= O) R ^ee , -CO ₂ H, -CO ₂ R ^ee , -OC (= O) R ^ee , -OCO ₂ R ^ee , -C (= O) N (R ^ff ) ₂ , -OC (= O) N (R ^ff ) ₂ , -NR ^ff C (= O) R ^ee , -NR ^ff CO ₂ R ^ee , -NR ^ff C (= O) N (R ^ff ) ₂ , -C (= NR ^ff ) OR ^ee , -OC (= NR ^ff ) R ^ee , -OC (= NR ^ff ) OR ^ee , -C (= NR ^ff ) N (R ^ff ) ₂ , -OC (= NR ^ff ) N (R ^ff ) ₂ , -NR ^ff C (= NR ^ff ) N (R ^ff ) ₂ , -NR ^ff SO ₂ R ^ee , -SO ₂ N (R ^ff ) ₂ , -SO ₂ R ^ee , -SO ₂ OR ^ee , -OSO ₂ R ^ee , -S (= O) R ^ee , -Si ( R ^ee ) ₃ , -OSi (R ^ee ) ₃ , -C (= S) N (R ^ff ) ₂ , -C (= O) SR ^ee , -C (= S) SR ^ee , -SC (= S) SR ^ee , -P (= O) (OR ^ee ) ₂ , -P (= O) (R ^ee ) ₂ , -OP (= O) (R ^ee ) ₂ , -OP (= O) (OR ^ee ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl , with each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently mo is substituted with groups 0, 1, 2, 3, 4 or 5 R ^gg , or two geminal substituents R ^dd can be connected to form = O or = S; where X ^- is a counterion;

each R ^{ee is} independently selected from C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl and 3 -10-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups;

each R ^{ff is} independently selected from hydrogen, C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, or two R ^ff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently substituted with groups 0, 1, 2, 3, 4 or 5 R ^gg ;

each R ^{gg is} independently halogen, —CN, —NO ₂ , —N ₃ , —SO ₂ H, —SO ₃ H, —OH, —OC _1-6 alkyl, —ON (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ₃ ⁺ X ^- , -NH (C _1-6 alkyl) ₂ ⁺ X ^- , -NH ₂ (C _1-6 alkyl ⁺ X ^- , -NH ₃ ⁺ X ^- , -N (OC _1-6 alkyl) (C _1-6 alkyl), -N (OH) (C _1-6 alkyl), -NH (OH), -SH, -SC _1-6 alkyl, -SS (C _1-6 alkyl), -C (= O) (C _1-6 alkyl), -CO ₂ H, -CO ₂ (C _1-6 alkyl), -OC (= O ) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C (= O) NH ₂ , -C (= O) N (C _1-6 alkyl) ₂ , -OC (= O ) NH (C _1-6 alkyl), -NHC (= O) (C _1-6 alkyl), -N (C _1-6 alkyl) C (= O) (C _1-6 alkyl), -NHCO ₂ ( C _1-6 alkyl), -NHC (= O) N (C _1-6 alkyl) ₂ , -NHC (= O) NH (C _1-6 alkyl), -NHC (= O) NH ₂ , -C ( = NH) O (C _1-6 alkyl), -OC (= NH) (C _1-6 alkyl), -OC (= NH) OC _1-6 alkyl, -C (= NH) N (C _1-6 alkyl) ₂ , -C (= NH) NH (C _1-6 alkyl), -C (= NH) NH ₂ , -OC (= NH) N (C _1-6 alkyl) ₂ , -OC (NH) NH (C _1-6 alkyl), -OC (NH) NH ₂ , -NHC (NH) N (C _1-6 alkyl) ₂ , -NHC (= NH) NH ₂ , -NHSO ₂ (C _1-6 alkyl) , -SO ₂ N (C _1-6 alkyl) ₂ , -SO ₂ NH (C _1-6 alkyl), -SO ₂ NH ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ OC _1-6 alkyl, —OSO ₂ C _1-6 alkyl, —SOC _1-6 alkyl, —Si (C _1-6 alkyl) ₃ , —OSi (C _1-6 alkyl) ₃ —C (= S) N ( C _1-6 alkyl) ₂ , C (= S) NH (C _1-6 alkyl), C (= S) NH ₂ , -C (= O) S (C _1-6 alkyl), -C (= S ) SC _1-6 alkyl, -SC (= S) SC _1-6 alkyl, -P (= O) (OC _1-6 alkyl) ₂ , -P (= O) (C _1-6 alkyl) ₂ , - OP (= O) (C _1-6 alkyl) ₂ , -OP (= O) (OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal substituents R ^gg can be linked to form = O or = S; where X ^- is a counterion.

each R ^{gg is} independently halogen, —CN, —NO ₂ , —N ₃ , —SO ₂ H, —SO ₃ H, —OH, —OC _1-6 alkyl, —ON (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ₃ ⁺ X ^- , -NH (C _1-6 alkyl) ₂ ⁺ X ^- , -NH ₂ (C _1-6 alkyl ⁺ X ^- , -NH ₃ ⁺ X ^- , -N (OC _1-6 alkyl) (C _1-6 alkyl), -N (OH) (C _1-6 alkyl), -NH (OH), -SH, -SC _1-6 alkyl, -SS (C _1-6 alkyl), -C (= O) (C _1-6 alkyl), -CO ₂ H, -CO ₂ (C _1-6 alkyl), -OC (= O ) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C (= O) NH ₂ , -C (= O) N (C _1-6 alkyl) ₂ , -OC (= O ) NH (C _1-6 alkyl), -NHC (= O) (C _1-6 alkyl), -N (C _1-6 alkyl) C (= O) (C _1-6 alkyl), -NHCO ₂ ( C _1-6 alkyl), -NHC (= O) N (C _1-6 alkyl) ₂ , -NHC (= O) NH (C _1-6 alkyl), -NHC (= O) NH ₂ , -C ( = NH) O (C _1-6 alkyl), -OC (= NH) (C _1-6 alkyl), -OC (= NH) OC _1-6 alkyl, -C (= NH) N (C _1-6 alkyl) ₂ , -C (= NH) NH (C _1-6 alkyl), -C (= NH) NH ₂ , -OC (= NH) N (C _1-6 alkyl) ₂ , -OC (NH) NH (C _1-6 alkyl), -OC (NH) NH ₂ , -NHC (NH) N (C _1-6 alkyl) ₂ , -NHC (= NH) NH ₂ , -NHSO ₂ (C _1-6 alkyl) , -SO ₂ N (C _1-6 alkyl) ₂ , -SO ₂ NH (C _1-6 alkyl), -SO ₂ NH ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ OC _1-6 alkyl, —OSO ₂ C _1-6 alkyl, —SOC _1-6 alkyl, —Si (C _1-6 alkyl) ₃ , —OSi (C _1-6 alkyl) ₃ , —C (= S) N (C _1-6 alkyl) ₂ , C (= S) NH (C _1-6 alkyl), C (= S) NH ₂ , -C (= O) S (C _1-6 alkyl), -C (= S) SC _1-6 alkyl, -SC (= S) SC _1-6 alkyl, -P (= O) (OC _1-6 alkyl) ₂ , -P (= O) (C _1-6 alkyl) ₂ , -OP (= O) (C _1-6 alkyl) ₂ , -OP (= O) (OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal substituents R ^gg can be linked to form = O or = S; where X ^- is a counterion.

[0045] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group to maintain electron neutrality. The anionic counterion can be monovalent (i.e., containing one formal negative charge). The anionic counterion can also be multivalent (i.e., containing more than one formal negative charge), for example, divalent or trivalent. Examples of counterions include halide ions (e.g. F ^- , Cl ^- , Br ^- , I ^- ), NO ₃ ^- , ClO ₄ ^- , OH ^- , H ₂ PO ₄ ^- , HSO ₄ ^- , sulfonate ions (e.g., methanesulfonate , trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate and the like), carboxylate ions (for example , acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate and the like), BF ₄ ^- , PF ₄ ^- , PF ₆ ^- , AsF ₆ ^- , SbF ₆ ^- , B [3,5- (CF ₃ ) ₂ C ₆ H ₃ ] ₄ ] ^- , BPh ₄ ^- , Al (OC (CF ₃ ) ₃ ) ₄ ^- and carborane anion (for example, CB ₁₁ H ₁₂ ^- or (HCB ₁₁ Me ₅ Br ₆ ) ^- ). Examples of counterions that may be multivalent include CO ₃ ^2- , HPO ₄ ^2- , PO ₄ ^3- , B ₄ O ₇ ^2- , SO ₄ ^2- , S ₂ O ₃ ^2- , carboxylate anions (e.g. tartrate , citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like) and carboranes.

[0046] The term "halo" or "halogen" refers to fluorine (fluorine, —F), chlorine (chlorine, —Cl), bromine (bromine, —Br), or iodine (iodine, —I).

[0047] "Acyl" refers to a moiety selected from the group consisting of —C (= O) R ^aa , —CHO, —CO ₂ R ^aa , —C (= O) N (R ^bb ) ₂ , —C ( = NR ^bb ) R ^aa , -C (= NR ^bb ) OR ^aa , -C (= NR ^bb ) N (R ^bb ) ₂ , -C (= O) NR ^bb SO ₂ R ^aa , -C (= S) N (R ^bb ) ₂ , -C (= O) SR ^aa, or -C (= S) SR ^aa , where R ^aa and R ^{bb are} as defined herein.

[0048] Nitrogen atoms can be substituted or unsubstituted depending on the valence and include primary, secondary, tertiary and quaternary nitrogen atoms. Examples of substituents on the nitrogen atom include, but are not limited to, hydrogen, -OH, -OR ^aa , -N (R ^cc ) ₂ , -CN, -C (= O) R ^aa , -C (= O) N (R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C (= NR ^bb ) R ^aa , -C (-NR ^cc ) OR ^aa , -C (= NR ^cc ) N (R ^cc ) ₂ , - SO ₂ N (R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C (= S) N (R ^cc ) ₂ , -C (= O) SR ^cc , -C ( = S) SR ^cc , -P (= O) (OR ^cc ) ₂ , -P (= O) (R ^aa ) ₂ , -P (= O) (N (R ^cc ) ₂ ) ₂ , C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, or two R ^cc the groups linked to the nitrogen atom are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, with each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently substituted with 0, 1, 2 groups, 3, 4 or 5 R ^dd , and R ^aa , R ^bb , R ^cc and R ^dd as defined above.

[0049] In some embodiments, the substituent present on the nitrogen atom is a nitrogen-protecting group (also called an amino-protecting group). The nitrogen protecting group includes, but is not limited to, -OH, -OR ^aa , -N (R ^cc ) ₂ , -C (= O) R ^aa , -C (= O) N (R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C (= NR ^cc ) R ^aa , -C (= NR ^cc ) OR ^aa , -C (= NR ^cc ) N (R ^cc ) ₂ , -SO ₂ N (R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C (= S) N (R ^cc ) ₂ , -C (= O) SR ^cc , -C (= S) SR ^cc , C _1-10 alkyl (eg aralkyl, heteroaralkyl), C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl groups wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd , and R ^aa , R ^bb , R ^cc and R ^dd as defined in this document. Nitrogen protecting groups are well known in the art and include those detailed in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0050] For example, nitrogen protecting groups such as amide groups (eg, -C (= O) R ^aa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3 -pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino) acetamide, 3- (p-hydroxyphenyl) propanamide 2-methyl-2- (o-nitrophenoxy) propanamide, 2-methyl-2- (o-phenylazophenoxy) propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o- (benzoyloxymethyl) benzamide.

[0051] Nitrogen protecting groups such as carbamate groups (eg -C (= OR) ^aa ) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9- (2-sulfo) fluorenylmethyl carbamate, 9- (2,7-dibromo) fluorenylmethylcarbamate, 2,7-di-tert-butyl- [9- (10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)] methylcarbamate (DBD-Tmoc), 4-methoxyphenacylcarbamate (Phenoc), 2,2,2-trichloroethylcarbamate (Troc), 2-trimethylsilylethylcarbamate (Teos), 2-phenylethylcarbamate (hZ), 1- (1-adamantyl) -1-methylethylcarbamate (Adpoc), 1,1-dimethyl- 2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1- (4-biphenylyl ) ethyl carbamate (Broc), 1- (3,5-di-tert-butylphenyl) -1-methylethylcarbamate (t-Bumeoc), 2- (2'- and 4'-pyridyl) ethyl carbamate (Pyos), 2- (N , N-dicyclohexylcarboxamido) ethyl carbamate, tert-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (IPCos), cinnamyl oc), 4-nitrocinnamylcarbamate (Noc), 8-quinolylcarbamate, N-hydroxypiperidinylcarbamate, alkyldithiocarbamate, benzylcarbamate (Cbz), p-methoxybenzylcarbamate (Moz), p-nitrobenzylcarbamate, p-nitrobenzylcarbamate, p-bromobenzyl chloride, p-bromobenzyl chloride 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethylcarbamate, diphenylmethylcarbamate, 2-methylthioethylcarbamate, 2-methylsulfonylethylcarbamate, 2- (p-toluenesulfonyl) ethylcarbamate, [2- (1,3] -dithianylcarbamate) Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Reos), 2-triphenylphosphonioisopropylcarbamate (Proc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxydbenzylcarbamate (dibenzylcarbamate) , 5-benzisoxazolylmethylcarbamate, 2- (trifluoromethyl) -6-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3,4-dimethoxy-6-nitrobenzylcarbamate, phenylcarbamate, phenylcarbamate tert-amylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, c iclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2,2-dimethoxyacylvinylcarbamate, o- (N, N-dimethylcarboxamido) benzylcarbamate, 1,1- (N, 1-) dimethyl-3-amido dimethylpropynylcarbamate, di (2-pyridyl) methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p- (p-methoxyphenylazato) 1-methylcarbamylcarbamate, methyl-1-methyl-carbamate -methyl 1- (3,5-dimethoxyphenyl) ethyl carbamate, 1-methyl-1- (p-phenylazophenyl) ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1- (4-pyridyl) ethyl carbamate, phenyl carbamate, p- (phenylazo) benzyl carbamate, 2,4,6-tri-tert-butyl phenyl carbamate, 4- (trimethylammonium) benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0052] Nitrogen protecting groups such as sulfonamide groups (eg, -S (= O) ₂ R ^aa ) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6, -trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms) , β-trimethylsilylethanesulfonamide (SES), 9-anthracene sulfonamide, 4- (4 ', 8'-dimethoxynaphthylmethyl) benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide and phenacylsulfonamide.

[0053] Other nitrogen protecting groups include, but are not limited to, (10) -acyl phenothiazinyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE) , 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5- dinitro-4-pyridone, N-methylamine, N-allylamine, N- [2- (trimethylsilyl) ethoxy] methylamine (SEM), N-3-acetoxypropylamine, N- (1-isopropyl-4-nitro-2-oxo 3-pyroolin-3-yl) amine, quaternary ammonium salts, N-benzylamine, N-di (4-methoxyphenyl) methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N - [(4-methoxyphenyl) diphenylmethyl ] amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N - [(2-pyridyl) mesityl] methyleneamine, N- (N ', N'-dimethylaminomethylene) amine, N, N'-isopropylideneamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N- (5-chloro-2-hydroxyphenyl) phenylmethyleneamine, N-cyclohexylideneamine, N- (5,5-dimethyl-3 -oxo-1-cyclohexenyl) amine, N-borane derivative, N-diphenylboronic acid derivative, N- [phenyl (pentaacylchromium or tungsten) acyl] amine, N-copper chelate, N-zinc chelate, N-nitroamine, N- nitrosamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkylphosphoramidates, dibenzylphosphoramidate, diphenylphosphoramidate, benzenesulfenamide, o-nitrobenzenesulfinamide, 2-nitrobenzenesulfenzolbenzene-amide -methoxybenzenesulfenamide, triphenylmethylsulfenamide and 3-nitropyridine sulfenamide (Npys).

Examples of oxygen atom substituents include, but are not limited to, -R ^aa , -C (= O) SR ^aa , -C (= O) R ^aa , -CO ₂ R ^aa , -C (= O) N (R ^bb ) ₂ , -C (= NR ^bb ) R ^aa , -C (= NR ^bb ) OR ^aa , - C (= NR ^bb ) N (R ^bb ) ₂ , -S (= O) R ^aa , -SO ₂ R ^aa , -Si (R ^aa ) ₃ , -P (R ^cc ) ₂ , -P (R ^cc ) ₃ ⁺ X ^- , -P (OR ^cc ) ₂ , -P (OR ^cc ) ₃ ⁺ X ^- , -P ( = O) (R ^aa ) ₂ , -P (= O) (OR ^cc ) ₂ and -P (= O) (N (R ^bb ) ₂ ) ₂ , where X-, R ^aa , R ^bb and R ^cc as defined in this document. In some embodiments, the oxygen substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups are well known in the art and include those detailed in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference. Examples of oxygen protecting groups include, but are not limited to, methyl, tert-butyloxycarbonyl (BOC or Boc), methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy) methyl (p-AOM), guaiacolmethyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), S-metoxytetrahydropyranyl (MTHP), 4-metoxytetrahydropyranyl -dioxide, 1 - [(2-chloro-4-methyl) phenyl] -4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3а, 4 , 5,6,7,7а-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran 2-yl, 1-ethoxyethyl, 1- {2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1- methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoro ethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl) ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide , diphenylmethyl, p, p-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di (p-methoxyphenyl) phenylmethyl, tri (p-methoxyphenyl) methyl, 4- (4'-bromophenyl) diphenacyl , 4 ', 4''- tris (4,5-dichlorophthalimidophenyl) methyl, 4,4', 4 '' - tris (levulinoyloxyphenyl) methyl, 4,4 ', 4''- tris (benzoyloxyphenyl) methyl, 3- {imidazol-1-yl) bis (4 ', 4''- dimethoxyphenyl) methyl, 1,1-bis (4-methoxyphenyl) -1-pyrenylmethyl, 9-anthryl, 9- (9-phenyl) xanthenyl, 9- (9-phenyl-10-oxo) anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl 8,8-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropyl DEIPS) , dimethylhexylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (DPMS), t-butylmethoxyphenylsilyl (DPMS), t-butylmethoxyphenylsilyl (DPMS), t-butylmethoxyphenylsilyl (DPMS), t-butylmethoxyphenylsilyl (DPMS), t-butylmethoxyphenylsilyl (DPMS), t-butylmethoxyphenylsilyl (DPMS), t-butylmethoxyphenylsilyl formate , trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio) pentanoate (levulinoyldithioacetal), pivaloate, benzodamantoate 4, pivaloate, benzodamantate phenyl benzoate, 2,4,6-trimethylbenzoate (mesitoate), alkylmethyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2- (trimethylsilyl) ethyl carbonate (TMSEC), 2- (trimethylsilyl) ethyl carbonate (TMSEC), 2 ) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Reos), alkylisobctyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyloxybenzyl oxycarbonate bonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyldithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethylmethyl) benzoate, 2-formylbenzene - (methylthiomethoxy) ethyl, 4- (methylthiomethoxy) butyrate, 2- (methylthiomethoxymethyl) benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetrpomethylbutyl) phenoxyacetate , 2,4-bis (1,1-dimethylpropyl) phenoxyacetate, chlorodiphenyl acetate, isobutyrate, monosuccinoate, (E) -2-methyl-2-butenoate, o- (methoxyacyl) benzoate, α-naphthoate, nitrate, alkyl N, N , N ', N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate and tosylate (Ts).

[0054] Examples of substituents on sulfur atoms include, but are not limited to, -R ^aa , -C (= O) SR ^aa , -C (= O) R ^aa , -CO ₂ R ^aa , -C (= O) N ( R ^bb ) ₂ , -C (= NR ^bb ) R ^aa , -C (= NR ^bb ) OR ^aa , -C (= NR ^bb ) N (R ^bb ) ₂ , -S (= O) R ^aa , -SO ₂ R ^aa , -Si (R ^aa ) ₃ , -P (R ^cc ) ₂ , -P (R ^cc ) ₃ ⁺ X ^- , -P (OR ^cc ) ₂ , -P (OR ^cc ) ₃ ⁺ X ^- , -P (= O) (R ^aa ) ₂ , -P (= O) (OR ^cc ) ₂ , b -P (= O) (N (R ^bb ) ₂ ) ₂ , where R ^aa , R ^bb and R ^cc as defined in this document.

представляет собой углеводородную цепь С₃. При использовании диапазона значений значение диапазона соответствует описанному в данном документе. Например, C_3-10 углеводородная цепь относится к углеводородной цепи, в которой число атомов цепи в самой короткой цепи атомов углерода непосредственно между двумя радикалами углеводородной цепи составляет 3, 4, 5, 6, 7, 8, 9 или 10. Углеводородная цепь может быть насыщенной (например, -(СН₂)₄-). Углеводородная цепь также может быть ненасыщенной и содержать одну или более связей С=С и/или С≡С в любом участке углеводородной цепи. Например, -СН=СН-(СН₂)₂-, -СН₂-С≡С-СН₂- и -С≡С-СН=СН- представляют собой все примеры незамещенной и ненасыщенной углеводородной цепи. В некоторых вариантах реализации углеводородная цепь является незамещенной (например, -С≡С- или -(СН₂)₄-). В некоторых вариантах реализации углеводородная цепь является замещенной (например, -СН(C₂H₅)- и -CF₂-). Любые два заместителя в углеводородной цепи могут быть соединены с образованием необязательно замещенного карбоциклильного, необязательно замещенного гетероциклильного, необязательно замещенного арильного или необязательно замещенного гетероарильного кольца. Например,

и

представляют собой все примеры углеводородной цепи. Напротив, в некоторых вариантах реализации

не входят в объем углеводородных цепей, описанных в данном документе. При замене цепочечного атома С_х углеводородной цепи гетероатомом полученную группу называют С_х углеводородной цепью, в которой атом цепи замещен гетероатомом, в отличие от C_x-1 углеводородной цепи. Например,

представляет собой C₃ углеводородную цепь, в которой один атом цепи замещен атомом кислорода.[0055] "Hydrocarbon chain" refers to a substituted or unsubstituted divalent alkyl, alkenyl, or alkynyl group. The hydrocarbon chain includes (1) one or more chains of carbon atoms directly between two radicals of the hydrocarbon chain; (2) optionally one or more hydrogen atoms in the chain (s) of carbon atoms; and (3) optionally one or more substituents (“non-chain substituents” that are not hydrogen) on the carbon chain (s). A chain of carbon atoms consists of sequentially linked carbon atoms ("chain atoms" or "carbon units") and does not include hydrogen atoms or heteroatoms. However, the non-chain substituent on the hydrocarbon chain can contain any atoms, including hydrogen atoms, carbon atoms, and heteroatoms. For example, the hydrocarbon chain -C ^A H (C ^B H ₂ C ^C H ₃ ) - contains one chain C ^A atom, one hydrogen atom on C ^A and a non-chain substituent - (C ^B H ₂ C ^C H ₃ ). The term "C _x hydrocarbon chain", where x is a positive integer, refers to a hydrocarbon chain that contains x chain atoms between two radicals of the hydrocarbon chain. If there is more than one possible x value, the smallest possible x value is used to define the hydrocarbon chain. For example, -CH (C ₂ H ₅ ) - is a C ₁ hydrocarbon chain, and

is a C ₃ hydrocarbon chain. When using a range of values, the value of the range is as described in this document. For example, a C _3-10 hydrocarbon chain refers to a hydrocarbon chain in which the number of chain atoms in the shortest carbon chain directly between two hydrocarbon chain radicals is 3, 4, 5, 6, 7, 8, 9, or 10. The hydrocarbon chain can be saturated (for example, - (CH ₂ ) ₄ -). The hydrocarbon chain can also be unsaturated and contain one or more C = C and / or C≡C bonds anywhere in the hydrocarbon chain. For example, —CH = CH- (CH ₂ ) ₂ -, —CH ₂ —C≡C — CH ₂ - and —C≡C — CH = CH— are all examples of an unsubstituted and unsaturated hydrocarbon chain. In some embodiments, the hydrocarbon chain is unsubstituted (eg, —C≡C— or - (CH ₂ ) ₄ -). In some embodiments, the hydrocarbon chain is substituted (eg, —CH (C ₂ H ₅ ) - and —CF ₂ -). Any two substituents on the hydrocarbon chain can be joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring. For instance,

and

represent all examples of the hydrocarbon chain. On the contrary, in some implementations

are not included in the scope of the hydrocarbon chains described in this document. When the chain atom C _{x of the} hydrocarbon chain is replaced by a heteroatom, the resulting group is referred to as a C _x hydrocarbon chain in which the chain atom is replaced by a heteroatom, in contrast to the C _x-1 hydrocarbon chain. For instance,

represents a C ₃ hydrocarbon chain in which one atom of the chain is replaced by an oxygen atom.

[0056] The term "leaving group" has its usual meaning in the field of organic synthesis and refers to an atom or group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g. acetoxy), arylcarbonyloxy, aryloxy, methoxy, N, O-dimethylhydroxylamino, pixyl and haloformates. In some cases, the leaving group is an activated substituted hydroxyl group (e.g., -OC (= O) SR ^aa , -OC (= O) R ^aa , -OCO ₂ R ^aa , -OC (= O) N (R ^bb ) ₂ , -OC (= NR ^bb ) R ^aa , -OC (= NR ^bb ) OR ^aa , -OC (= NR ^bb ) N (R ^bb ) ₂ , -OS (= O) R ^aa , -OSO ₂ R ^aa , -OP (R ^cc ) ₂ , -OP (R ^cc ) ₃ , -OP (= O) ₂ R ^aa , -OP (= O) (R ^aa ) ₂ , -OP (= O) (OR ^cc ) ₂ , -OP (= O) ₂ N (R ^bb ) ₂ and -OP (= O) (NR ^bb ) ₂ , where R ^aa , R ^bb and R ^{cc are} as defined herein). In some cases, the leaving group is a sulfonic acid ester such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), -OS (= O) ₂ (CF ₂ ) ₃ CF ₃ (nonaflate, -ONf) or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. The leaving group can also be a phosphine oxide (eg, obtained from the Mitsunobu reaction) or an internal leaving group such as epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium particles, diazonium salts, and copper particles.

[0057] The term "pharmaceutically acceptable salt" refers to those salts that are medically suitable for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic reaction and the like, and have a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by Berge et al. In J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from the corresponding inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzosulfonate, benzoate, bisulfate, borate, butyrate, camphor, camphorsulfonate, citrate, cyclopentane propionate, bigluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, gisulfonate , hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthyl sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, 3 pers. phenylate, pecipate , phosphate, picrate, pivalate, propionate, stearate, succinate, sulfates, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C _1-4 alkyl) ₄ salts. Examples of alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Additionally, pharmaceutically acceptable salts include, as appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed with counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

[0058] The term "solvate" refers to forms of a compound that are bound to a solvent, usually by a solvolysis reaction. The specified physical connection may include a hydrogen bond. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be obtained, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both liquid phase solvates and isolatable solvates. Typical solvates include hydrates, ethanolates, and methanolates.

[0059] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in the hydrate of a compound is in a certain ratio to the number of molecules of the compound in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R⋅x H ₂ O, where R is a compound and x is a number greater than 0. This compound is capable of forming more than one type of hydrate, including, for example, monohydrates (x is 1) , lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrates (R⋅0.5H ₂ O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R⋅2H ₂ O) and hexahydrates (R⋅ 6H ₂ O)).

[0060] The term "tautomers" or "tautomeric" refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valence (eg, change from a single bond to a double bond, a triple bond to single bond or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., a reaction providing a tautomeric pair) can be catalyzed by acid or base. Examples of tautomerization include tautomerization of keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine- (other) enamine.

[0061] It should also be understood that compounds that have the same molecular formula, but differ in the nature or sequence of attachment of atoms or the arrangement of atoms in space are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers".

[0062] Stereoisomers that are not mirror images of each other are called "diastereomers", and those that are mirror images of each other that are not in space aligned are called "enantiomers". If a compound has an asymmetric center, for example, it is associated with four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by an absolute configuration of an asymmetric center and is described by the rules of the R- and S-sequence of Kahn and Prelog or the direction in which the molecule rotates the plane of polarized light, denoted as right rotation or left rotation (that is, as (+) or (-) - isomers , respectively). The chiral compound can exist as a single enantiomer or as a mixture of enantiomers. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0063] The term "polymorphs" refers to the crystalline form of a compound (or a salt, hydrate, or solvate thereof) in a specified crystal structure. All polymorphs have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystalline form, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystalline form to dominate. Different polymorphs of a compound can be obtained by crystallization under different conditions.

[0064] The term "prodrugs" refers to compounds that have cleavable groups and become, by solvolysis or under physiological conditions, the compounds described herein, pharmaceutically active in vivo. Examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters, and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, however, in the acid-sensitive form, they often have the advantages of solubility, tissue compatibility, or delayed release in mammals (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as, for example, esters prepared by reacting a parent acid with an appropriate alcohol, or amides prepared by reacting an acid parent compound with a substituted or unsubstituted amine or acid anhydrides or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic side chain groups of the compounds described herein are specific prodrugs. In some cases, it is required to prepare double ester type prodrugs such as (acyloxy) alkyl ethers or ((alkoxycarbonyl) oxy) alkyl ethers. C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, aryl, C ₇ -C ₁₂ substituted aryl, and C ₇ -C ₁₂ arylalkyl esters of the compounds described herein may be preferred.

[0065] The term "inhibiting", "inhibiting", "inhibiting" or "inhibitor" refers to the ability of a compound to reduce, slow down, stop, or prevent the activity of a particular biological process in a cell as compared to a carrier.

[0066] When a compound, pharmaceutical composition, method, use, or kit is referred to as "selectively", "specifically" or "competitively" binds the first protein, the compound binds the first protein with a higher binding affinity (e.g., at least about 2 times, not less than about 5 times, not less than about 10 times, not less than about 30 times, not less than about 100 times, not less than about 1000 times, or not less than about 10,000 times higher) than the binding of a second protein or other different from the first protein. When a compound is referred to as "selectively", "specifically" or "competitively" modulating (e.g., increasing or inhibiting) the activity of a protein, the compound modulates the activity of the protein to a greater extent (e.g., at least about 2-fold, at least about 5-fold, at least about 10 times, at least about 30 times, at least about 100 times, at least about 1000 times, or at least about 10,000 times) than the activity of at least one protein that differs from the first protein ...

[0067] The term "aberrant activity" refers to activity deviating from normal activity. The term "increased activity" refers to activity above normal.

[0068] The terms "composition" and "composition" are used interchangeably.

[0069] The term "subject" to whom the medication is prescribed refers to a human (i.e., a man or woman of any age group, for example, a pediatric patient (for example, an infant, child, or adolescent) or an adult subject (for example, youth, middle-aged and older age)) or non-human animals. The term "patient" refers to a person in need of treatment for a disease.

[0070] The terms "administer," "administration," or "administration," as used herein, refer to the implantation, absorption, ingestion, injection, inhalation, or otherwise administered to a subject of a compound or composition thereof described herein.

[0071] The terms "treating" and "treating" refer to reversing, ameliorating, delaying the onset or inhibiting the development of a disease described herein. In some embodiments, treatment can be performed after one or more signs or symptoms of a disease develop or become apparent. In other embodiments, treatment can be performed in the absence of signs or symptoms of disease. For example, treatment can be administered to a susceptible subject prior to the onset of symptoms (eg, based on a history of symptoms and / or exposure to a pathogen) to delay or prevent the onset of disease. Treatment can also be continued after symptoms have stopped, for example, to delay or prevent relapse.

[0072] The terms "condition", "disease" and "disorder" are used interchangeably.

[0073] An "effective amount" of a compound described herein refers to an amount sufficient to produce the desired biological response, ie, treatment of a disease. As those skilled in the art will appreciate, the effective amount of a compound described herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the route of administration, and the age and health of the subject. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is for prophylactic treatment. In some embodiments, the effective amount is a single dose of a compound described herein. In some embodiments, the effective amount is multiple doses of a compound described herein.

[0074] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic effect in treating a disease or to delay or minimize one or more symptoms associated with a disease. A therapeutically effective amount of a compound means that amount of a therapeutic agent, alone or in combination with other drugs, that provides a therapeutic effect in the treatment of a disease. The term "therapeutically effective amount" can include an amount that improves the overall treatment, reduces or eliminates the symptoms, signs, or causes of the disease, and / or enhances the therapeutic efficacy of another therapeutic agent.

[0075] A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent disease, one or more disease-related symptoms, or recurrence of the disease. A prophylactically effective amount of a compound means that amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic effect in the prevention of disease. The term "prophylactically effective amount" can include an amount that improves the overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0076] The term "proliferative disease" refers to a disease that arises from abnormal growth or germination as a result of an increase in cell numbers (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative disease can be associated with: 1) pathological proliferation of normally resting cells; 2) pathological migration of cells from their normal localization (for example, metastases of neoplastic cells); 3) pathological expression of a mutated gene (eg, p53, Ras, and EGFR); or 4) pathological angiogenesis, as in proliferative retinopathy and tumor metastasis. Examples of proliferative diseases include oncological diseases (ie, "malignant neoplasms"), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.

[0077] The terms "neoplasm" and "tumor" are used interchangeably herein and refer to an abnormal mass of tissue in which the growth of mass outpaces and does not match the growth of normal tissue. A neoplasm or tumor can be “benign” or “malignant” depending on the following characteristics: the degree of cellular differentiation (including morphology and functionality), growth rate, local invasion and metastasis. A “benign neoplasm” is usually well differentiated, characterized by slower growth than a malignant neoplasm, and remains localized at the site of origin. In addition, a benign neoplasm does not have the ability to infiltrate, germinate or metastasize to distant sites. Examples of benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordones, senile angiomas, seborrheic keratoses, lentigo, and sebaceous hyperplasia. In some cases, certain "benign" tumors can subsequently cause malignant neoplasms, which may be due to additional genetic changes in a subset of neoplastic tumor cells, and these tumors are called "precancerous neoplasms". An example of a precancerous neoplasm is teratoma. In contrast, "malignant neoplasm" is usually poorly differentiated (anaplasia) and is characterized by rapid growth, accompanied by progressive infiltration, invasion and destruction of surrounding tissue. In addition, a malignant neoplasm usually has the ability to metastasize to distant sites. The term "metastasis", "metastatic" or "metastasizing" refers to the spread or migration of cancer cells from a primary or original tumor to another organ or tissue and is usually identified by the presence of a "secondary tumor" or "secondary cell mass" of the tissue type of the primary or original tumor. and not the tissue of an organ or tissue in which a secondary (metastatic) tumor is located. For example, breast cancer that has migrated to the lungs, liver and bones is considered metastatic breast cancer and includes breast cancer cells growing in the lungs, liver, and bone.

[0078] The term "cancer" refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See, for example, Stedman's Medical Dictionary, 25th ed .; Hensyl ed .; Williams & Wilkins: Philadelphia, 1990. Examples of cancers include, but are not limited to, hematological malignancies. Examples of cancers include, but are not limited to, bladder cancer; breast cancer (eg, breast adenocarcinoma, papillary breast carcinoma, breast cancer, medullary breast carcinoma); cervical cancer; urethral cancer; vaginal cancer and vulvar cancer (eg, Paget's disease of the vulva).

Brief Description of Drawings

[0079] Non-limiting embodiments of the present invention are described by way of examples with reference to the accompanying drawings, which are schematic and not drawn to scale. In the drawings, each identical or nearly identical component is typically represented by a single number. For clarity, not every component is labeled in every figure, and not every component of every embodiment is shown where illustration is not necessary for those skilled in the art to understand the invention.

[0080] Figure 1 is a graph of tumor volume change in a mouse model study of the efficacy of xMCF-7 xenograft in human breast cancer treated with Example Compound 25 versus fulvestrant, GDC-0810 and AZD9496.

[0081] Figure 2 is a graph showing the change in tumor volume in the study of the efficacy of xMCF-7 xenograft human breast cancer in a mouse model when treated with examples of compounds 12, 21 and 25 compared to AZD9496.

[0082] Figure 3 is a graph showing the efficacy of combination treatment of Example Compound 25 with CDK4 / 6 Inhibitor palbociclib on tumor volume change in a mouse model of the efficacy of xMCF-7 xenograft in human breast cancer.

Detailed description of the invention

[0083] The present invention provides selective estrogen receptor inhibitors (SERIs), for example, compounds of formula (I) that selectively bind the estrogen receptor and result in receptor degradation. The compounds described herein are useful for lowering estrogen receptor levels (wild type or mutated) and treating a disease associated with a steroid hormone such as estrogen (eg, breast cancer such as ER-positive breast cancer). Examples of SRIED compounds disclosed herein successfully induce ER degradation and inhibit the growth of MCF-7 cancer cell, an ER-positive human breast cancer cell line. In addition, the present description provides pharmaceutical compositions, kits, methods of using the SIER compounds for the treatment of any of the target diseases described herein.

Selective estrogen receptor inhibitors

[0084] One aspect of the present invention relates to the SIEV compounds described herein, as well as their pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs. These compounds are useful for the treatment and / or prevention of proliferative diseases (such as ER-positive breast cancer) or diseases associated with ER in a subject.

[0085] In some embodiments, the compound is a compound of Formula (I):

где R¹-R⁷, A, W, а и n как описаны в данном документе, или представляет собой фармацевтически приемлемую соль, сольват, гидрат, полиморф, сокристалл, таутомер, стереоизомер, изотопически меченое производное или пролекарство.

where R ¹ -R ⁷ , A, W, a and n as described herein, or is a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug.

[0086] In Formula (I), A and W are in a tricyclic ring. In some embodiments, A may be -CR ^A = or -N =. In some embodiments, A may be —CR ^A =, where R ^{A is} as defined herein. In some embodiments, R ^A can be hydrogen. In some embodiments, R ^A may be substituted or unsubstituted C _1-6 alkyl (eg, methyl, ethyl, or propyl). In one example, A may be —CH =. In another example, A may represent -CMe =. In other embodiments, A may be -NH =.

[0087] In some embodiments, W may be —NH—. In some embodiments, W may be —O—. In some embodiments, W may be -S-.

[0088] Formula (I) includes one or more R ¹ . In some embodiments, a is 1. In some embodiments, a is 2. In some embodiments, a is 3. In some embodiments, at least one R ¹ may be hydrogen. In some embodiments, at least one R ¹ may be halogen (eg, F, Cl, Br, or I). In some embodiments, at least one R ¹ may be fluoro. In some embodiments, at least one R ¹ may be chlorine. In some embodiments, at least one R ¹ may be substituted or unsubstituted C _1-6 alkyl (eg, methyl, ethyl, or propyl). In some embodiments, at least one R ¹ may be —CF ₃ . In some embodiments, at least one R ¹ may be —OR ^A , where R ^{A is} as defined herein. In some embodiments, at least one R ¹ may be —OMe. In some embodiments, at least one R ¹ may be —OEt. In some embodiments, at least one R ¹ may be —CN.

[0089] In Formula (I), in some embodiments, R ² may be hydrogen. In some embodiments, R ² can be substituted or unsubstituted C _1-6 alkyl (eg, methyl, ethyl, or propyl). In some embodiments, R ² can be methyl. In some embodiments, R ² can be ethyl. In some embodiments, R ² can be propyl. In some embodiments, R ² may be —CF ₃ . In some embodiments, R ² may be a substituted or unsubstituted carbocyclyl (eg, substituted or unsubstituted 3-7 membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). In some embodiments, R ² can be cyclopropyl. In some embodiments, R ² can be cyclobutyl.

[0090] In Formula (I), in some embodiments, R ³ and / or R ⁴ may be hydrogen. In some embodiments, R ³ and / or R ⁴ may be halogen (eg, F, Cl, Br, or I). In some embodiments, R ³ and / or R ⁴ may be fluoro. In some embodiments, R ³ and / or R ⁴ may be substituted or unsubstituted C _1-6 alkyl (eg, methyl, ethyl, or propyl). In some embodiments, R ³ and / or R ⁴ may be methyl. In some embodiments, R ³ and / or R ⁴ may be ethyl. In some embodiments, R ³ and / or R ⁴ may be propyl. In some embodiments, one of R ³ and R ⁴ can be fluoro and the other of R ³ and R ⁴ can be substituted or unsubstituted C _1-6 alkyl (eg, methyl). In some embodiments, one of R ³ and R ⁴ can be fluoro and the other of R ³ and R ⁴ can be methyl. In some embodiments, both R ³ and R ⁴ may be fluoro. In some embodiments, both R ³ and R ⁴ can be methyl. In some embodiments, R ³ and / or R ⁴ may be substituted or unsubstituted carbocyclyl (eg, substituted or unsubstituted 3-7 membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). In some embodiments, R ³ and / or R ⁴ can be substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted 5-10 membered monocyclic or bicyclic heterocyclic ring, where one or two atoms in the heterocyclic ring are independently nitrogen, oxygen or sulfur). In some embodiments, R ³ and / or R ⁴ may be substituted or unsubstituted aryl (eg, phenyl or benzyl). In some embodiments, R ³ and / or R ⁴ can be substituted or unsubstituted 5-7 membered monocyclic heteroaryl, with one, two, three, or four atoms in the heteroaryl ring system independently being nitrogen, oxygen, or sulfur). In some embodiments, R ³ and / or R ⁴ can be —OR ^A where R ^{A is} as defined herein (eg —OH, —O (substituted or unsubstituted C _1-6 alkyl) (eg —OMe)) ... In some embodiments, R ³ and / or R ⁴ may be —N (R ^B ) ₂ , where R ^{B is} as defined herein (eg, —NH ₂ ).

[0091] In Formula (I), in some embodiments, R ⁵ and / or R ⁶ may be hydrogen. In some embodiments, R ⁵ and / or R ⁶ may be halogen (eg, F, Cl, Br, or I). In some embodiments, R ⁵ and / or R ⁶ may be chlorine. In some embodiments, R ⁵ and / or R ⁶ can be substituted or unsubstituted C _1-6 alkyl (eg, methyl, ethyl, or propyl). In some embodiments, both R ⁵ and R ⁶ may be halogen. In some embodiments, both R ⁵ and R ⁶ can be fluoro. In some embodiments, both R ⁵ and R ⁶ can be chlorine. In some embodiments, one of R ⁵ and R ⁶ may be chlorine and the other may be fluorine. In some embodiments, one of R ⁵ and R ⁶ can be fluoro and the other can be substituted or unsubstituted C _1-6 alkyl. In some embodiments, one of R ⁵ and R ⁶ may be chloro and the other may be substituted or unsubstituted C _1-6 alkyl.

[0092] In Formula (I), in some embodiments, R ⁷ may be hydrogen. In some embodiments, R ⁷ can be halogen (eg, F, Cl, Br, or I). In some embodiments, R ⁷ can be substituted or unsubstituted C _1-6 alkyl (eg, methyl, ethyl, or propyl). In some embodiments, R ⁷ may be a compound of the formula —CH ₂ R ^a , where R ^a is halogen. In some embodiments, R ⁷ may be —CH ₂ F. In some embodiments, R ⁷ may be —OR ^A where R ^{A is} as defined herein (e.g., —OH, —O (substituted or unsubstituted C _1-6 alkyl) (for example, -OMe)). In some embodiments, R ⁷ may be —N (R ^B ) ₂ , where R ^{B is} as defined herein (eg, —NH ₂ ).

[0093] In Formula (I), in some implementations, n may be 1. In some implementations, n may be 2. In some implementations, n may be 3. In some implementations, n may be 4.

[0094] In some embodiments, the described compound has Formula (II):

where R ¹ -R ⁴ , R ⁸ , R ^A1 , R ^A2 , A, W, and a are as described herein, or represent a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug. [0095] In Formula (II), A and W are in a tricyclic ring. In some embodiments, A may be -CR ^A = or -N =. In some embodiments, A may be —CR ^A =, where R ^{A is} as defined herein. In some embodiments, R ^A can be hydrogen. In some embodiments, R ^A can be substituted or unsubstituted C _1-6 alkyl (eg, methyl, ethyl, or propyl). In one example, A may be —CH =. In one example, A may be —CMe =. In other embodiments, A may be -NH =.

[0096] In some embodiments, W may be —NH—. In some embodiments, W may be —O—. In some embodiments, W may be -S-.

[0097] Formula (II) includes one or more R ¹ . In some embodiments, a is 1. In some embodiments, a is 2. In some embodiments, a is 3. In some embodiments, at least one R ¹ may be hydrogen. In some embodiments, at least one R ¹ may be halogen (eg, F, Cl, Br, or I). In some embodiments, at least one R ¹ may be fluoro. In some embodiments, at least one R ¹ may be chlorine. In some embodiments, at least one R ¹ may be substituted or unsubstituted C _1-6 alkyl (eg, methyl, ethyl, or propyl). In some embodiments, at least one R ¹ may be substituted or unsubstituted methyl. In some embodiments, at least one R ¹ may be —CF ₃ . In some embodiments, at least one R ¹ may be substituted or unsubstituted ethyl. In some embodiments, at least one R ¹ may be substituted or unsubstituted propyl. In some embodiments, at least one R ¹ may be —OR ^A where R ^{A is} as defined herein. In some embodiments, at least one R ¹ may be —OH. In some embodiments, at least one R ^A may be substituted or unsubstituted C _1-6 alkyl. In some embodiments, at least one R ¹ may be —OMe. In some embodiments, at least one R ¹ may be —CN.

[0098] In Formula (II), in some embodiments, R ² may be hydrogen. In some embodiments, R ² can be substituted or unsubstituted C _1-6 alkyl (eg, methyl, ethyl, or propyl). In some embodiments, R ² can be substituted or unsubstituted methyl. In some embodiments, R ² may be —CF ₃ . In some embodiments, R ² can be substituted or unsubstituted ethyl. In some embodiments, R ² can be substituted or unsubstituted propyl. In some embodiments, R ² can be a substituted or unsubstituted carbocyclyl (eg, a substituted or unsubstituted 3-7 membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). In some embodiments, R ² may be substituted or unsubstituted cyclopropyl.

[0099] In Formula (II), in some embodiments, R ³ and / or R ⁴ may be hydrogen. In some embodiments, R ³ and / or R ⁴ may be halogen (eg, F, Cl, Br, or I). In some embodiments, R ³ and / or R ⁴ may be fluoro. In some embodiments, both R ³ and R ⁴ may be fluoro. In some embodiments, R ³ and / or R ⁴ may be substituted or unsubstituted C _1-6 alkyl (eg, methyl, ethyl, or propyl). In some embodiments, R ³ and / or R ⁴ may be methyl. In some embodiments, one of R ³ and R ⁴ can be fluoro and the other can be methyl. In some embodiments, one of R ³ and R ⁴ can be fluoro and the other can be hydrogen. In some embodiments, one of R ³ and R ⁴ can be methyl and the other can be hydrogen. In some embodiments, R ³ and / or R ⁴ may be substituted or unsubstituted carbocyclyl (eg, substituted or unsubstituted 3-7 membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). In some embodiments, R ³ and / or R ⁴ can be substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted 5-10 membered monocyclic or bicyclic heterocyclic ring, where one or two atoms in the heterocyclic ring are independently nitrogen, oxygen or sulfur). In some embodiments, R ³ and / or R ⁴ may be substituted or unsubstituted aryl (eg, phenyl or benzyl). In some embodiments, R ³ and / or R ⁴ can be substituted or unsubstituted 5-7 membered monocyclic heteroaryl, with one, two, three, or four atoms in the heteroaryl ring system independently being nitrogen, oxygen, or sulfur). In some embodiments, R ³ and / or R ⁴ can be —OR ^A where R ^{A is} as defined herein (eg —OH, —O (substituted or unsubstituted C _1-6 alkyl) (eg —OMe)) ... In some embodiments, R ³ and / or R ⁴ may be —N (R ^B ) ₂ , where R ^{B is} as defined herein (eg, —NH ₂ ). In some embodiments, R ³ and R ⁴ may be taken together with intermediate atoms to form a substituted or unsubstituted carbocyclyl (eg, a substituted or unsubstituted 3-7 membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). In some embodiments, R ³ and R ⁴ can be taken together with intermediate atoms to form substituted or unsubstituted cyclopropyl. In some embodiments, R ³ and R ⁴ can be taken together with intermediate atoms to form unsubstituted cyclopropyl, and R ⁸ can be fluoro. In some embodiments, R ³ and R ⁴ can be taken together with intermediate atoms to form unsubstituted cyclopropyl, and R ⁸ can be methyl. In some embodiments, R ³ and R ⁴ can be taken together with intermediate atoms to form a substituted or unsubstituted heterocyclyl (e.g., a substituted or unsubstituted 5-10 membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms on the heterocyclic ring independently represent are nitrogen, oxygen or sulfur).

[00100] In Formula (II), in some embodiments, R ⁸ may be hydrogen. In some embodiments, R ⁸ may be halogen (eg, F, Cl, Br, or I). In some embodiments, R ⁸ can be fluoro. In some embodiments, R ⁸ may be substituted or unsubstituted methyl. In some embodiments, R ⁸ can be methyl.

[00101] In Formula (II), in some embodiments, R ^A1 and / or R ^A2 may be substituted or unsubstituted C _1-6 alkyl (eg, methyl, ethyl, or propyl). In some embodiments, R ^A1 and / or R ^A2 may be substituted or unsubstituted methyl. In some embodiments, R ^A1 and / or R ^A2 may be substituted or unsubstituted ethyl. In some embodiments, R ^A1 and / or R ^A2 can be substituted or unsubstituted propyl. In some embodiments, R ^A1 and / or R ^A2 may be chlorine. In some embodiments, R ^A1 and / or R ^A2 may be fluoro. In some embodiments, either R ^A1 or R ^A2 can be chlorine. In some embodiments, both R ^A1 and R ^A2 can be chlorine. In some embodiments, one of R ^A1 or R ^A2 may be fluoro, and the other of R ^A1 and R ^A2 may be selected from the group consisting of substituted or unsubstituted alkyl, chlorine, and fluoro. In some embodiments, one of R ^A1 or R ^A2 may be fluoro, and the other of R ^A1 and R ^A2 may be substituted or unsubstituted _C1-6 alkyl (eg, methyl, ethyl, or propyl). In some embodiments, one of R ^A1 or R ^A2 may be fluoro and the other of R ^A1 and R ^A2 may be methyl. In some embodiments, one of R ^A1 or R ^A2 can be fluoro and the other of R ^A1 and R ^A2 can be chloro. In some embodiments, both R ^A1 and R ^A2 can be fluoro.

[00102] In some embodiments, the compound of Formula (I) may have the formula of the compounds described herein, or be a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[00103] In some embodiments, a compound of Formula (II) may have the formula of the compounds described herein, or be a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[00104] The compounds described herein can be prepared from readily available starting materials using methods known in the art. It is clear that in cases where typical or preferred conditions for the implementation of the method are indicated (i.e., the reaction temperature, time, molar ratios of the reagents, solvents, pressure, etc.), other conditions for the implementation of the method can also be used, unless otherwise indicated. Optimal reaction conditions may vary depending on the particular reagents or solvent used, however, such conditions can be determined by one of ordinary skill in the art using conventional optimization techniques. Chemicals used in the above synthesis methods may include, for example, solvents, reagents, catalysts, protecting groups, and deprotecting reagents. The methods described above may also further include steps both before and after the steps specifically described herein to add or remove suitable protecting groups to ultimately provide the synthesis of the compounds. In addition, different steps of the synthesis can be performed in a different sequence in order to obtain the desired compounds. Synthetic chemical transformations and methodology of protecting groups (introduction and removal of protecting groups) suitable for the synthesis of compounds are known in the art and include, for example, described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TWGreene and PGMWuts, Protective Groups in Organic Synthesis, 3 ^rd Ed, John Wiley and Sons (1999).; L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) et seq.

[00105] The compounds of Formula (I) and Formula (II) provided in this invention can be prepared from readily available starting materials using conventional methods and methods. Examples of schematic illustrations for the synthesis of compounds in accordance with the invention described herein are given below. In cases where typical or preferred conditions for the implementation of the method are indicated (i.e., the reaction temperature, time, molar ratios of reagents, solvents, pressure, and so on), other conditions for the implementation of the method can also be used, unless otherwise indicated. Optimal reaction conditions may vary depending on the particular reagents or solvent used, however, such conditions can be determined by one of ordinary skill in the art using conventional optimization techniques.

[00106] The compounds described herein, eg, the compounds of Formula (I), can be prepared according to General Scheme A. Compounds A1 are commercially available or can be synthesized by standard transformations known to those skilled in the organic / medicinal chemistry. Compounds A3 can be obtained by the reaction of Pikte-Spengler A1 with aldehyde A2 (X = I, Br or Cl). Compound A5 can be obtained by alkylation of A3 with A4. Alternatively, A5 can be prepared by alkylating A1 with A4, followed by the Pictet-Spengler A6 reaction with the aldehyde A2. Copper or palladium-activated C-O bond formation of compound A5 with ethylene glycol can provide compound A7. The transformation of the OH group A7 into a leaving group followed by the substitution of A8 is capable of providing (I).

Scheme A. An example of a scheme for the preparation of compounds of Formula (I)

[00107] Compounds of Formula (II) can be prepared according to General Scheme B. Compounds B3 are commercially available or can be prepared by standard transformations known to those of ordinary skill in the organic / medicinal chemistry. Compounds B2 can be prepared by alkylating A1 with B1. As a result of the Pictet-Spengler B2 reaction with the aldehyde B3, B4 can be obtained. Saponification of B4 to (II) can generally be carried out with an alkali metal hydroxide in aqueous or mixed aqueous / organic solvents.

Scheme B. Example of a Scheme for the Preparation of Compounds of Formula (II)

[00108] Alternatively, the compounds of Formula (II) can be prepared according to General Scheme C. By reaction of Pikte-Spengler B2 with an aldehyde C1 (X = I, Br or Cl), C2 can be obtained. Compounds C4 can be prepared by a palladium-catalyzed Heck reaction between C2 and C3. Saponification of C4 to (II), as a rule, can be carried out with an alkali metal hydroxide in aqueous or mixed aqueous / organic solvents.

Scheme C. Example of a Scheme for the Preparation of Compounds of Formula (II)

Pharmaceutical compositions and kits

[00109] The present invention provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition described herein includes a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The disclosed pharmaceutical compositions are useful in the treatment and / or prevention of proliferative diseases (eg ER-positive breast cancer) or ER-related diseases.

[00110] In some embodiments, a cell contacted with an effective amount of a compound or pharmaceutical composition described herein is in vitro. In some embodiments, the contacting cell is ex vivo. In some embodiments, the described cell is in vivo. In some embodiments, the described cell is a malignant cell (eg, a malignant breast cancer cell).

[00111] In some embodiments, a compound described herein is provided in an effective amount in a pharmaceutical composition. In some embodiments, the effective amount is a therapeutically effective amount (eg, an amount effective to treat a proliferative disease in a subject in need of treatment). In some embodiments, the proliferative disease is cancer, for example ER-positive breast cancer. In some embodiments, the effective amount is a prophylactically effective amount (e.g., an amount effective to prevent a proliferative disease in a subject in need thereof and / or to maintain a subject in need thereof in remission of a proliferative disease).

[00112] The pharmaceutical compositions described herein can be prepared by any method known in the field of pharmacology. In general, methods of preparation include forming a bond of a compound described herein (i.e., an "active ingredient") with a carrier or excipient and / or one or more other accessory ingredients, and then, if necessary and / or as desired, shaping and / or packaging the product in the required single or multiple dose.

[00113] Pharmaceutical compositions can be obtained, packaged and / or sold in bulk, as a single dose and / or as multiple single doses. A “single dose” is a discrete amount of a pharmaceutical composition containing a predetermined amount of an active ingredient. The amount of active ingredient is usually equal to the dose of active ingredient that is administered to the subject and / or a convenient portion of such a dose, such as half or one third of the dose.

[00114] The relative amounts of active ingredient, pharmaceutically acceptable excipient and / or any additional ingredients in the pharmaceutical composition described herein will vary depending on the characteristics, growth and / or condition of the subject being treated, as well as the route of administration. compositions. The composition may contain from 0.1 to 100% (w / w) of the active ingredient.

[00115] Pharmaceutically acceptable excipients used in the preparation of the proposed pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, agents for improving tablet disintegration, binding agents, preservatives, buffering agents, lubricants agents and / or oils. Auxiliary substances such as cocoa butter and suppository bases, colorants, coating agents, sweeteners, flavors and flavors may also be present in the composition.

[00116] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredients, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol , 1,3-butylene glycol, dimethylformamide, oils (for example, cottonseed, peanut, corn, germ oil, olive, castor and sesame oils), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of fatty acids and sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and flavoring agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor ^®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[00117] Injectables, eg, sterile injectable aqueous or oily suspensions, can be prepared by methods known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injection solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Suitable carriers and solvents include water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile fixed oils are typically used as solvent or suspension medium. For this purpose, you can use any soft fixed oil, including synthetic mono - or diglycerides. In addition, fatty acids such as oleic acid are used for the preparation of injections.

[00118] Injectable formulations can be sterilized, for example, by filtration through a bacteria filter or by including sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately prior to use.

[00119] In order to prolong the effect of the drug, it is most often preferable to slow down the absorption of the drug by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with low water solubility. The rate of drug absorption also depends on the rate of dissolution, which, in turn, may depend on the size of the crystals and the crystalline form. Alternatively, delayed absorption of a parenterally administered drug is achieved by dissolving or suspending the drug in an oil vehicle.

[00120] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In said solid dosage forms, the active ingredient is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or additives such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum, c) humectants such as glycerin, d) disintegrants such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates, and sodium carbonate, e) a solution of an inhibiting agent such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate i, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. The dosage form in the form of capsules, tablets and pills may also contain a buffering agent.

[00121] Solid compositions of a similar type can also be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally contain opacifiers and may be formulated to release the active ingredient (s) only or preferably in a specific part of the intestinal tract, optionally in a delayed manner. Examples of encapsulating compositions that can be used include polymeric materials and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[00122] The active ingredient can be in microencapsulated form with one or more excipients as mentioned above. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings, and other coatings well known in the art of pharmaceutical development. In these solid dosage forms, the active ingredient can be mixed with at least one inert diluent such as sucrose, lactose or starch. These dosage forms may include, as is common practice, additional substances other than inert diluents, for example, tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. Dosage forms in the form of capsules, tablets and pills may contain buffering agents. They may optionally contain opacifiers and may be formulated to release the active ingredient (s) only or preferably in a specific part of the intestinal tract, optionally in a delayed manner. Examples of encapsulating agents that can be used include polymeric materials and waxes.

[00123] The descriptions of the pharmaceutical compositions disclosed herein generally relate to pharmaceutical compositions that are suitable for administration to humans, however, these compositions are generally suitable for administration to animals of all kinds. Modification of pharmaceutical compositions suitable for administration to humans to prepare compositions for administration to various animals is well known and a moderate veterinarian pharmacologist can design and / or carry out such a modification by routine experimentation.

[00124] The compounds described herein are generally formulated in a single dose for ease of administration and dosage uniformity. However, it should be understood that the total daily dose of the compounds described herein is medically prescribed by the attending physician. The specific level of therapeutically effective dose for any particular subject or organism depends on a variety of factors, including: the disease to be treated, as well as the severity of the disease; the activity of the particular active ingredient used; the specific composition used; the age, body weight, general health, sex and nutrition of the patient; the time of administration, the route of administration and the rate of elimination of the particular compound used; duration of treatment; drugs used in combination or concurrently with the particular compound used; and other similar factors well known in medicine.

[00125] Also included in the present invention are kits (eg, pharmaceutical bags). Kits in accordance with the invention may include a pharmaceutical composition or compound described herein, as well as a container (eg, vial, ampoule, bottle, syringe and / or dispensing package or other suitable container). In some embodiments, the kits may optionally further include a second container containing a pharmaceutical adjuvant for dilution or a suspension of a pharmaceutical composition or compound described herein. In some embodiments, a pharmaceutical composition or compound described herein provided in a first container and in a second container is combined to form a single unit dosage form.

[00126] In some embodiments, the kit described herein includes a first container containing the composition or pharmaceutical composition described herein. In some embodiments, the kit described herein is useful for treating a proliferative disease (e.g., ER-positive breast cancer) in a subject in need of treatment and / or preventing a proliferative disease in a subject in need thereof. In some embodiments, the SSRIs described herein are useful for treating diseases and / or disorders associated with a steroid hormone such as estrogen.

[00127] In some embodiments, the kit described herein further includes instructions for use of the compound or pharmaceutical composition included in the kit. The kit may also include information as required by a regulatory agency such as the US Food and Drug Administration (FDA). In some embodiments, the information included in the kits is an instruction manual for the preparation. In some embodiments, kits and instructions are provided for treating a proliferative disease in a subject in need of treatment and / or preventing a proliferative disease in a subject in need thereof. The kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

Treatment methods

[00128] As shown in the Examples below, the exemplary SIEV compounds described herein successfully induced ER degradation and inhibited the growth of ER-positive breast cancer cells and had better clearance of human hepatocytes than a drug of the same class such as fulvestrant, and also drugs currently in clinical trials such as GDC-0810 and AZD9496. In studies in mice, these compounds have also shown superior pharmacokinetic profiles (eg, clearance, half-life and AUC) compared to drugs currently in clinical use or in clinical trials.

[00129] Accordingly, the present invention provides methods of treating a proliferative disease and / or a disease associated with a steroid hormone, such as estrogen, in a subject in need of treatment, the methods comprising administering to the subject an effective amount (eg, a therapeutically effective amount) of a compound, or its pharmaceutical composition as described herein.

[00130] Another aspect of the present invention relates to methods for preventing a proliferative disease in a subject in need thereof, the methods comprising administering to the subject an effective amount (eg, a prophylactically effective amount) of a compound or a pharmaceutical composition thereof described herein.

[00131] The disclosed compounds and pharmaceutical compositions are useful in the treatment and / or prevention of proliferative diseases. In some embodiments, the proliferative disease is cancer. In some embodiments, the proliferative disease is breast cancer. In some embodiments, the proliferative disease is a gynecological disease or cancer associated with ER, such as ovarian cancer, cervical or endometrial cancer, and breast cancer, in particular ER-positive breast cancer.

[00132] In some embodiments, the method described herein further comprises administering to the subject an additional pharmaceutical agent. In some embodiments, the method described herein further comprises contacting the biological sample with an additional pharmaceutical agent. In some embodiments, the method described herein further comprises contacting the tissue with an additional pharmaceutical agent. In some embodiments, the method described herein further comprises contacting the cell with an additional pharmaceutical agent. In some embodiments, the method described herein further comprises radiation therapy, immunotherapy, and / or transplantation (eg, bone marrow transplantation).

[00133] The compounds and compositions provided herein can be administered by any route, including enteral (eg, oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricular, percutaneous, intradermal, rectal, intravaginal, intravaginal , local (in the form of powders, ointments, creams and / or drops). Routes specifically contemplated include oral administration, intravenous administration (eg, systemic intravenous injection), regional administration through the bloodstream and / or lymph, and / or direct administration to the affected area. In general, the most appropriate route of administration depends on many factors, including the nature of the agent (eg, its stability in the gastrointestinal tract) and / or the condition of the subject (eg, the subject's ability to tolerate oral administration).

[00134] The exact amount of a compound required to provide a therapeutically effective amount varies from subject to subject, depending, for example, on the species, age and general condition of the subject, the severity of side effects or disorders, the type of particular compound, route of administration, and the like. An effective amount can be included in a single dose (eg, a single oral dose) or multiple doses (eg, multiple oral doses). In some embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, any two of the multiple doses comprise different or substantially the same amounts of a compound described herein. In some embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the frequency of administration of multiple doses to the subject, or administration of multiple doses to a tissue or cell is three doses per day, two doses per day, one dose per day, one dose every two days, one dose every three days, or one dose weekly. In some embodiments, the frequency of administration of multiple doses to a subject or administration of multiple doses to a tissue or cell is one dose per day. In some embodiments, the frequency of administration of multiple doses to a subject or administration of multiple doses to a tissue or cell is two doses per day. In some embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the time period between the first dose and the last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks. one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years or the lifetime of a subject, biological sample, tissue or cell. In some embodiments, the time period between the first dose and the last dose of the multiple doses is three months, six months, or one year. In some embodiments, the time period between the first dose and the last dose of the plurality of doses is the lifetime of the subject, biological sample, tissue, or cell. In some embodiments, a dose (e.g., a single dose or any multi-dose dose) described herein comprises, independently of 1 to 3 mg, 3 to 10 mg, 10 to 30 mg, 30 to 100 mg, 100 up to 300 mg, from 300 to 1000 mg, or from 1 g to 10 g, inclusive, of the compound described herein. In some embodiments, the dosage described herein contains, regardless of 3 mg to 10 mg, inclusive of the compound described herein. In some embodiments, the dosage described herein contains, independently of 10 mg to 30 mg, inclusive of the compound described herein. In some embodiments, the dosage described herein contains, independently of 30 mg to 100 mg, inclusive of the compound described herein. In some embodiments, the dosage described herein contains, regardless of 100 mg to 300 mg, inclusive of the compound described herein. In some embodiments, the dose described herein contains, independently of 300 mg to 1000 mg, inclusive of the compound described herein.

[00135] These dose ranges are recommended for administration of the proposed pharmaceutical compositions to adult patients. The amount to be administered to, for example, a child or adolescent, can be determined by a practitioner or person skilled in the art and can be the same as that administered to an adult, or less.

[00136] The compound or composition described herein can be administered in combination with one or more additional pharmaceutical agents (eg, therapeutically and / or prophylactically active agents) useful for the treatment and / or prevention of a proliferative disease. The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potential and / or efficacy) in treating a proliferative disease in a subject in need of treatment and / or for preventing a proliferative disease in a subject, needing it), improve bioavailability, improve safety, reduce drug resistance, reduce and / or alter metabolism, inhibit excretion and / or modify distribution in a subject, biological sample, tissue or cell. It should also be borne in mind that the applied therapy may achieve the desired effect for the same disorder and / or may have different effects. In some embodiments, a pharmaceutical composition described herein, including a compound described herein and an additional pharmaceutical agent, exhibits a synergistic effect not found in a pharmaceutical composition that includes only the compound or only the additional pharmaceutical agent, but not both.

[00137] The compound or composition can be administered concurrently, before or after one or more additional pharmaceutical agents that may be useful, for example, as a combination therapy for the treatment and / or prevention of a proliferative disease. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactic active agents. Pharmaceutical agents include small organic molecules such as drug compounds (for example, compounds approved for use in humans or animals by the US Food and Drug Administration as stipulated in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, antibodies, small molecules associated with proteins such as antibodies, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleotides, oligotides lipids, hormones, vitamins and cells. In some embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating a proliferative disease. In some embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for preventing a proliferative disease. In some embodiments, the additional pharmaceutical agent is a pharmaceutical agent approved by a regulatory body (eg, US FDA) for the treatment and / or prevention of a proliferative disease. Each additional pharmaceutical agent can be administered at a dose and / or schedule specified for that pharmaceutical agent. Additional pharmaceutical agents can also be administered together with each other and / or with a compound or composition described herein in a single dose, or administered separately in different doses. The particular combination for use in a course of treatment takes into account the compatibility of the compound described herein with the additional pharmaceutical agent (s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is contemplated that the additional pharmaceutical agent (s) in combination will be used in amounts not exceeding those in which it is used alone. In some embodiments, the amounts used in combination are less than the amounts used individually.

[00138] In some embodiments, the additional pharmaceutical agent is an anti-proliferative agent (eg, an anti-cancer agent, eg, immuno-oncological agents (eg, anti-PD-1 antibody) or cells (eg, CAR-T cells)). In some embodiments, the additional pharmaceutical agent is an anti-angiogenesis agent, an anti-inflammatory agent, an immunosuppressant, an antibacterial agent, an antiviral agent, a cardiovascular agent, a cholesterol-lowering agent, an anti-diabetic agent, an anti-allergic agent, an analgesic agent, or a combination thereof. In some embodiments, the compounds or pharmaceutical compositions described herein can be administered in combination with cancer therapy, including, but not limited to, targeted therapy (e.g., an inhibitor that blocks mTOR signaling), cell therapy, surgery, radiation therapy, immunotherapy, and chemotherapy (eg, docetaxel, doxorubicin).

[00139] Without further elaboration, it is believed that one skilled in the art based on the above description can use the present invention to its fullest extent. The following specific embodiments of the present invention are therefore to be construed as illustrative only, and not limiting in any way the rest of the description. All publications cited herein are incorporated by reference for the purposes or subject matter of the invention recited herein.

Examples of

[00140] The following examples are provided for a more complete understanding of the present invention. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions and methods disclosed in this document and should in no way be construed as limiting their scope.

[00141] Example 1: Synthesis of Compound 1 and its derivatives

[00142] Stage 1. Synthesis 1-2

[00143] A solution of (2R) -1- (1H-indol-3-yl) propan-2-amine (2 g, 11.48 mmol), acetic acid (1 ml) and 2,6-difluoro-4-iodobenzaldehyde (3 g, 11.19 mmol) in toluene (20 ml) was stirred at 80 ° C for 12 h. The resulting mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1 / 100-1 / 10) as eluent to give the desired product (2 g, 42% yield).

[00144] Stage 2. Synthesis 1-3

[00145] To a solution of 1-2 (2 g, 4.71 mmol) in 1,4-dioxane (20 ml) were added N, N-diisopropylethylamine (920 mg, 7.08 mmol) and 2,2-difluoropropyl trifluoromethanesulfonate (1 , 61 g, 7.06 mmol). The resulting solution was stirred at 100 ° C for 12 hours. The reaction mixture was cooled to room temperature and then quenched with water (50 ml). The mixture was extracted with ethyl acetate (50 ml × 3). The organic phase was washed with brine (50 ml) and concentrated in vacuo to give the desired product (1.5 g, untreated).

[00146] Stage 3. Synthesis 1-4

[00147] To a solution of 1-3 (500 mg, 1.00 mmol) in ethane-1,2-diol (5 ml) was added copper iodide (94.6 mg, 0.50 mmol), 1,10-phenanthroline ( 18 mg, 0.10 mmol) and cesium carbonate (649 mg, 1.99 mmol). The resulting mixture was stirred at 100 ° C for 2 hours. After cooling to room temperature, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (30 ml × 3). The organic phase was washed with brine (20 ml) and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1 / 100-1 / 10) as eluent to obtain the desired product (200 g, 46% yield).

[00148] Stage 4. Synthesis 1-5

[00149] To a solution of 1-4 (50 mg, 0.11 mmol) in tetrahydrofuran (2 ml) were added triethylamine (13.9 mg, 0.14 mmol) and 4-methylbenzene-1-sulfonyl chloride (26 mg, 0, 14 mmol). The resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with water (10 ml) and extracted with ethyl acetate (10 ml × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the desired product (50 mg, 74% yield).

[00150] Stage 5. Synthesis 1

[00151] A solution of 1-5 (50 mg, 0.08 mmol), 3- (fluoromethyl) azetidine (20.47 mg, 0.23 mmol) and cesium carbonate (41.5 mg, 0.13 mmol) in acetonitrile (2 ml) was stirred at 80 ° C for 12 h. After cooling to room temperature, the mixture was diluted with water (10 ml) and was extracted with ethyl acetate (10 ml × 3). The organic phase was concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1 / 100-1 / 5) as eluent to obtain the desired product (19.7 g, 46% yield). LCMS (ES, m / z): a508.4. ¹ NMR (300 MHz, CDCl ₃ , ppm): δ 7.41 (d, J = 6.9 Hz, 1 H, 7.19-7.17 (d, J = 7.2 Hz, 1 H), 7.03-6.95 (m, 2 H) 6.64-6.59 (m, 2 H), 5.24 (s, 1 H), 4.61 (d, J = 3.9 Hz, 1 H), 4.46 (d, J = 3.9 Hz, 1 H), 4.18-4.10 (m, 4 H), 3.96-3.90 (m, 2 H), 3 , 57-3.55 (m, 1 H), 3.44-3.41 (m, 2 H), 3.31-3.10 (m, 1 H), 3.10-2.95 (m , 2 H), 2.65-2.60 (m, 2 H), 1.42 (t, J = 18.9 Hz, 3 H), 1.13 (d, J = 6.6 Hz, 3 H).

[00152] Similarly, the following additional compounds were prepared in accordance with the invention.

[00153] Example 2: Synthesis of Compound 13B and its derivatives

[00154] Stage 1. Synthesis 13-1

[00155] To a solution of 5-fluoro-1H-indole-3-carbaldehyde (2.0 g, 12.3 mmol, 1.00 eq.) In toluene (20 ml) was added ammonium acetate (1.14 g, 14, 8 mmol, 1.20 eq.) And nitroethane (24 ml) at room temperature. The resulting solution was stirred at 130 ° C for 5 hours. The solid was filtered off and the filter cake was washed with ethyl acetate (10 ml × 3). The filtrate was concentrated in vacuo, the residue was diluted with water (40 ml) and was extracted with ethyl acetate (35 ml × 3). The combined organic layer was washed with brine (40 ml × 3), dried over anhydrous sodium sulfate and concentrated in vacuo to give 5-fluoro-3 - [(1Z) -2-nitroprop-1-en-1-yl] 1H-indole ( 2.23 g, 83%) as a yellow solid.

[00156] Stage 2. Synthesis 13-2

[00157] To a solution of 5-fluoro-3 - [(1Z) -2-nitroprop-1-en-1-yl] -1H-indole (2.0 g, 9.1 mmol, 1.00 eq.) In tetrahydrofuran (50 ml), lithium aluminum hydride (1.37 g, 36.0 mmol, 4.00 eq.) was added at 0 ° C, the reaction mixture was stirred at 65 ° C for 1 hour. After cooling to room temperature, the reaction was quenched by the addition of water (1.4 ml), aqueous sodium hydroxide solution (4.2 ml, 10%). The solid was filtered off and the filter cake was washed with tetrahydrofuran (15 ml × 3). The filtrate was concentrated in vacuo to give 1- (5-fluoro-1H-indol-3-yl) propan-2-amine (1.8 g, 102%) as a brown oil.

[00158] Stage 3. Synthesis 13-3

[00159] To a solution of 1- (5-fluoro-1H-indol-3-yl) propan-2-amine (1.0 g, 5.2 mmol, 1.00 eq.) In 1,4-dioxane (24 ml) were added N, N-diisopropylethylamine (1.01 g, 7.8 mmol, 1.50 eq.) and 2-fluoro-2-methylpropyl trifluoromethanesulfonate (1.28 g, 5.7 mmol, 1.10 eq.) ... The resulting solution was stirred at 70 ° C overnight. The reaction was quenched by adding water (30 ml), the mixture was extracted with ethyl acetate (30 ml × 3). The combined organic layer was washed with brine (30 ml × 3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1: 4) as eluent to give [1- (5-fluoro-1H-indol-3-yl) propan-2-yl] (2-fluoro-2- methylpropyl) amine (610 mg, 44%) as a brown solid.

[00160] Stage 4. Synthesis 13-4

[00161] To a solution of [1- (5-fluoro-1H-indol-3-yl) propan-2-yl] (2-fluoro-2-methylpropyl) amine (510 mg, 1.92 mmol, 1.00 eq .) in toluene (20 ml) were added acetic acid (460 mg, 7.67 mmol, 4.00 eq.) and 2,6-difluoro-4-iodobenzaldehyde (514 mg, 1.92 mmol, 1.00 eq.) ). The resulting solution was stirred at 80 ° C overnight. The reaction was quenched by the addition of water (15 ml), the mixture was extracted with ethyl acetate (20 ml × 3), the combined organic layer was washed with brine (20 ml × 3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1:50) as eluent to give 1- (2,6-difluoro-4-iodophenyl) -6-fluoro-2- (2-fluoro-2-methylpropyl) -3-methyl-1H, 2H, 3H, 4H, 9H-pyrido [3,4-b] indole (800 mg, 81%) as a light yellow solid.

[00162] Stage 5. Synthesis 13-5

[00163] To a solution of 1- (2,6-difluoro-4-iodophenyl) -6-fluoro-2- (2-fluoro-2-methylpropyl) -3-methyl-1H, 2H, 3H, 4H, 9H-pyrido [3,4-b] indole (680 mg, 1.32 mmol, 1.00 eq.) In ethylene glycol (20 ml) under N _{2 was} added cesium carbonate (859 mg, 2.64 mmol, 2.00 eq. ) and copper iodide (126 mg, 0.66 mmol, 0.50 eq.). The resulting solution was stirred overnight at 100 ° C, the reaction mixture was cooled to room temperature. The reaction was then quenched by the addition of water (20 ml) and the mixture was extracted with ethyl acetate (30 ml × 3). The combined organic layer was washed with brine (40 ml × 3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1: 1) as eluent to give 2- [3,5-difluoro-4- [6-fluoro-2- (2-fluoro-2-methylpropyl) -3 -methyl-1H, 2H, 3H, 4H, 9H-pyrido [3,4-b] indol-1-yl] phenoxy] ethan-1-ol (600 mg, 101%) as a light yellow oil.

[00164] Step 6. Synthesis 13-6

[00165] To a solution of 2- [3,5-difluoro-4- [6-fluoro-2- (2-fluoro-2-methylpropyl) -3-methyl-1H, 2H, 3H, 4H, 9H-pyrido [3 , 4-b] indol-1-yl] phenoxy] ethan-1-ol (550 mg, 1.22 mmol, 1.00 eq.) In dichloromethane (16 ml), triethylamine (247 mg, 2.44 mmol, 2.00 equiv.) And N, N-dimethylaminopyridine (15 mg, 0.12 mmol, 0.10 equiv.) Under N ₂ . 4-methylbenzene-1-sulfonyl chloride (280 mg, 1.45 mmol, 1.20 eq.) Was added at 0 ° C. The resulting solution was stirred at room temperature for 2 hours. The reaction was quenched by the addition of water (15 ml), the mixture was extracted with dichloromethane (20 ml × 3). The combined organic layer was washed with brine (30 ml × 3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1: 5) as eluent to give 2- [3,5-difluoro-4- [6-fluoro-2- (2-fluoro-2-methylpropyl) -3 -methyl-1H, 2H, 3H, 4H, 9H-pyrido [3,4-b] indol-1-yl] phenoxy] ethyl 4-methylbenzene-1-sulfonate (400 mg, 54%) as light yellow oils.

[00166] Stage 7. Synthesis 13

[00167] To a solution of 2- [3,5-difluoro-4- [6-fluoro-2- (2-fluoro-2-methylpropyl) -3-methyl-1H, 2H, 3H, 4H, 9H-pyrido [3 , 4-b] indol-1-yl] phenoxy] ethyl 4-methylbenzene-1-sulfonate (300 mg, 0.49 mmol, 1.00 eq.) In acetonitrile (18 ml), cesium carbonate (1.13 g, 3.48 mmol, 7.00 eq.) under N ₂ . Then 3- (fluoromethyl) azetidine trifluoroacetyl (462 mg, 2.48 mmol, 5.00 eq.) Was added at 0 ° C. The resulting solution was stirred at 80 ° C overnight. The reaction mixture was cooled to room temperature, the reaction was quenched by the addition of water (20 ml), the mixture was extracted with ethyl acetate (20 ml × 3). The combined organic layer was washed with brine (30 ml × 3), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by preparative HPLC [column, Xbridge, RP18, 19 * 150 mm; mobile phase. A: NH ₄ CO ₃ (aq.) (5 mmol / l). B: acetonitrile (70% - 90% in 8 min); speed, 25 ml / min; Detector, 254 nm] to afford 111 (100 mg, 38%) as a white solid. Compound 111 was isolated by chiral preparative HPLC [chiral column, IA-3, 250 mm x 20 mm, 5 μm; mobile phase. A: hexane (91%), B: ethanol (9%); speed, 20 ml / min; Detector, 254 nm] to obtain 13A (retention time: 13.91 min) and 13B (retention time: 22.37 min).

[00168] 13A: 13.9 mg, white solid. Chiral HPLC [Column: IA, 100 mm, 4.6 mm, 0.6 ml / min, mobile phase: hexane (0.1% DEA) / IPA; Gradient: 10% IPS; Detector: 254 nm], retention time = 7.22 min. LCMS (ES, m / z) [M + H] ⁺ : 522.40. ¹ NMR (300 MHz, CD ₃ OD, ppm) δ 7.13 (dd, J = 4.5 Hz, J = 8.7 Hz, 1 H), 7.07 (dd, J = 2.4 Hz, 6.9 Hz, 1H), 6.76 (td, J = 2.4 Hz, 9.0 Hz, 1 H), 6.58-6.53 (m, 2 H), 5.19 (s, 1H), 4.58 (d, J = 7.2 Hz, 1 H), 4.42 (d, J = 7.2 Hz, 1 H), 4.01 (t, J = 6.8 Hz, 2 H), 3.71-3.65 (m, 1H), 3.55 (t, J = 10.0 Hz, 2 H), 3.24 (t, J = 10.0 Hz, 2H), 3.06-2.99 (m, 1H), 2.91-2.86 (m, 3H), 2.57 (dd, J = 2.7 Hz, J = 14.7 Hz, 1H), 2 , 40 (dd, J = 15.0 Hz, J = 26.4 Hz, 1H), 1.23-1.10 (m, 9H).

[00169] 13B: 17.8 mg, white solid. Chiral HPLC [Column: IA, 100 mm, 4.6 mm, 0.6 ml / min, mobile phase: hexane (0.1% DEA) / IPA; Gradient: 10% IPS; Detector: 254 nm], retention time = 12.34 min. LCMS (ES, m / z) [M + H] ⁺ : 522.40. ¹ NMR (300 MHz, CD ₃ OD, ppm) δ 7.13 (dd, J = 4.2 Hz, J = 8.7 Hz, 1 H), 7.07 (dd, J = 2.4 Hz, 6.9 Hz, 1H), 6.77 (td, J = 2.4 Hz, 9.0 Hz, 1 H), 6.58-6.53 (m, 2 H), 5.19 (s, 1H), 4.58 (d, J = 5.4 Hz, 1 H), 4.42 (d, J = 5.7 Hz, 1 H), 4.01 (t, J = 5.7 Hz, 2 H), 3.71-3.65 (m, 1H), 3.56 (t, J = 7.8 Hz, 2 H), 3.24 (t, J = 7.8 Hz, 2H), 3.06-2.99 (m, 1H), 2.91-2.86 (m, 3H), 2.57 (dd, J = 2.7 Hz, J = 14.7 Hz, 1H), 2 , 40 (dd, J = 15.0 Hz, J = 26.4 Hz, 1H), 1.23-1.10 (m, 9H).

[00170] Similarly, the following additional compounds were prepared in accordance with the invention.

[00171] Example 3: Synthesis of Compound 16B

[00172] Stage 1. Synthesis 16-1

[00173] To a solution of 3-bromo-1,1,1-trifluoropropan-2-one (10 g, 52.37 mmol) in trichloromethane (60 ml) at room temperature was added a solution of NH ₂ OH 2HCl (5, 46 g, 78.56 mmol) in water (10 ml). The resulting solution was stirred at 65 ° C for 24 hours. After cooling to room temperature, the mixture was diluted with water (30 ml) and extracted with dichloromethane (40 ml × 3). The organic phase was washed with brine (50 ml × 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by distillation under reduced pressure (0.1 MP), the fraction was collected at 70-80 ° C to obtain the target product (4.6 g, 43% yield) as a colorless oil.

[00174] Stage 2. Synthesis 16-2

[00175] To a solution of (E) -N- (3-bromo-1,1,1-trifluoropropan-2-ylidene) hydroxylamine (4 g, 19.42 mmol) in methyl tert-butyl ether (800 ml) was added 1H-indole (9.1 g, 77.68 mmol) and sodium carbonate (12.5 g, 116.83 mmol). The resulting solution was stirred at room temperature for 1 day. The solid was filtered off and the filter cake was washed with dichloromethane (50 ml × 2). The filtrate was washed with brine (50 ml × 2), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product (4 g, 85% yield) as a light yellow oil.

[00176] Stage 3. Synthesis of 16-3

[00177] To a solution of 16-2 (4 g, 16.52 mmol) in tetrahydrofuran (100 ml) at 0 ° C. was added lithium aluminum hydride (2.6 g, 68.51 mmol) in portions. The mixture was stirred at 0 ° C for 10 minutes and then at 70 ° C overnight. The reaction mixture was cooled to room temperature and quenched by the addition of saturated aqueous NH ₄ Cl (200 ml). The solid was filtered off and the filter cake was washed with ethyl acetate (100 ml × 2). The filtrate was extracted with ethyl acetate (100 ml). The organic phase was washed with brine (200 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1/3) as eluent to give the title product (2.4 g, 64% yield).

[00178] Stage 4. Synthesis 16-4

[00179] To a solution of 16-3 (264 mg, 1.16 mmol) and 2-fluoro-2-methylpropyl trifluoromethanesulfonate (430 mg, 1.92 mmol) in 1,4-dioxane (1 ml) was added 18-crown-6 (422 mg, 1.60 mmol) and N, N-diisopropylethylamine (620 mg, 4.80 mmol). The resulting solution was stirred at 110 ° C for 26 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (50 ml) and washed with brine (30 ml × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash preparative HPLC under the following conditions [Column: C18 silica gel; Mobile phase: MeCN / H ₂ O (0.1% TFA)), 25% -70% MeCN; Detector: 254 nm] to obtain the target product (270 mg).

[00180] Stage 5. Synthesis 16-5

[00181] To a solution of 16-4 (600 mg, 1.98 mmol) in toluene (6 ml) were added 2,6-difluoro-4-iodobenzaldehyde (590 mg, 2.20 mmol) and acetic acid (0.2 ml ). The reaction mixture was then stirred at 80 ° C. for 16 hours. After cooling, the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1/29) as eluent to give the title product (600 g, 55% yield).

[00182] Step 6. Synthesis 16-6

[00183] To a solution of 16-5 (600 mg, 1.09 mmol) in ethane-1,2-diol (12 ml) was added 1,10-phenanthroline (20 mg, 0.11 mmol), CuI (105 mg, 0.55 mmol) and cesium carbonate (711 mg, 2.18 mmol). The reaction mixture was stirred at 100 ° C for 2 h. After cooling, the mixture was diluted with water (100 ml) and extracted with ethyl acetate (100 ml × 2). The organic phase was washed with brine (100 ml × 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1: 2) as eluent to give the title product (270 g, 51% yield).

[00184] Step 7. Synthesis 16-7

[00185] To a solution of 16-6 (270 mg, 0.56 mmol) in tetrahydrofuran (10 ml) were added p-toluenesulfonyl chloride (128 mg, 0.67 mmol), 4-dimethylaminopyridine (13 mg, 0.11 mmol) and triethylamine (68 mg, 0.67 mmol). The reaction mixture was stirred at 30 ° C for 16 h before being concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (2: 1) as eluent to give the title product (120 g, 34% yield).

[00186] Stage 8. Synthesis 16

[00187] To a solution of 3- (fluoromethyl) azetidine (261 mg, 1.39 mmol) in acetonitrile (10 ml) was added cesium carbonate (1.02 g, 3.13 mmol) and 16-7 (100 mg, 0, 16 mmol). The reaction mixture was stirred at 80 ° C for 16 h. After cooling, the solids were filtered off and the filtrate was concentrated in vacuo. The residue was purified by flash preparative HPLC [Column, C18 silica gel; mobile phase (A: H ₂ O (0.05% NH ₄ HCO ₃ ), B: MeCN), 40% MeCN to 69% MeCN in 10 minutes; speed: 80 ml / min; Detector, UV 254 nm]. The crude product was then purified by preparative HPLC [Column, Xbridge RP C18, 19 × 150 nm; Mobile phase (A: H ₂ O (0.05% NH ₄ HCO ₃ ), B: MeCN), MeCN = 50% to MeCN = 80% in 8 min, rate: 25 ml / min; Detector, UV 254 nm] to obtain the target product as a racemate (25 mg, 29% yield).

[00188] Racemic product 16 was separated using chiral preparative HPLC [Column, IA; Mobile phase, 12% ethanol / hexane (0.1% diethylamine); 20 ml / min; 18 minutes; Detector, 254 nm] to obtain target products.

[00189] Compound (16A): Retention time = 7.7 min. LCMS (ES, m / z) 558.20 [M + H] ⁺ ; ¹ NMR (300 MHz, CD ₃ OD, ppm): δ 7.45 (d, J = 6.9 Hz, 1 H), 7.19 (d, J = 6.9 Hz, 1 H), 7, 06-6.96 (m, 2 H), 6.56 (d, J = 11.1 Hz, 2 H), 5.52 (s, 1 H), 4.55 (d, J = 5.4 Hz, 1 H), 4.39 (d, J = 5.4 Hz, 1 H), 4.28-4.16 (m, 1 H), 4.01-3.98 (m, 2 H) , 3.63-3.47 (m, 2 H), 3.37-3.22 (m, 4 H), 3.19-3.02 (m, 2 H), 2.91-2.59 (m, 3 H), 1.28-1.09 (m, 6 H).

[00190] Compound (16B): Retention time = 14.5 min. LCMS (ES, m / z) 558.20 [M + H] ⁺ ; ¹ H-NMR (300 MHz, CD ₃ OD, ppm): δ 7.44 (d, J = 6.9 Hz, 1 H), 7.20 (d, J = 7.2 Hz, 1 H), 7.05-6.96 (m, 2 H), 6.56 (d, J = 13.8 Hz, 2 H), 5.52 (s, 1 H), 4.55 (d, J = 5 , 4 Hz, 1 H), 4.40 (d, J = 5.4 Hz, 1 H), 4.28-4.02 (m, 1 H), 4.01-3.98 (m, 2 H), 3.58-3.53 (m, 2 H), 3.34-3.25 (m, 4 H), 3.13-3.10 (m, 2 H), 2.92-2 , 88 (m, 2 H), 2.73-2.59 (m, 1 H), 1.28-1.09 (m, 6H).

[00191] Example 4: Synthesis of Compounds 17A and 17B and Their Derivatives

[00192] Stage 1. Synthesis 17-2

[00193] To a solution of 1- (1-benzofuran-3-yl) propan-2-amine (1.2 g, 6.85 mmol) in 1,4-dioxane (40 ml) was added N, N-diisopropylethylamine (2 , 6 g, 20.12 mmol) and 2-fluoro-2-methylpropyl trifluoromethanesulfonate (1.54 g, 6.87 mmol). The resulting solution was stirred at 75 ° C for 16 hours. After cooling, the mixture was diluted with ice water (100 ml) and was extracted with ethyl acetate (100 ml × 3). The organic phase was washed with brine (100 ml × 2), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product (1.5 g, 88% yield).

[00194] Stage 2. Synthesis 17-3

[00195] To a mixture of 17-2 (820 mg, 3.29 mmol) in toluene (30 ml) were added acetic acid (593 mg, 9.88 mmol) and 2,6-difluoro-4-iodobenzaldehyde (883 mg, 3 , 29 mmol). The resulting solution was stirred at 100 ° C for 2 days. After cooling, the mixture was diluted with ice water (100 ml) and was extracted with ethyl acetate (50 ml × 3). The organic phase was washed with brine (50 ml x 2), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product (0.3 g, 18% yield).

[00196] Stage 3. Synthesis of 17-4

[00197] To a mixture of 17-3 (300 mg, 0.60 mmol) in ethane-1,2-diool (10 ml) were added cesium carbonate (585 mg, 1.80 mmol) and copper (I) iodide (114, 2 mg). The resulting solution was stirred at 100 ° C overnight. After cooling, the mixture was diluted with saturated ammonium chloride solution (30 ml) and was extracted with ethyl acetate (30 ml × 3). The organic phase was washed with brine (30 ml × 2), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product (150 mg, 58% yield).

[00198] Stage 4. Synthesis 17-5

[00199] To a solution of 17-4 (150 mg, 0.35 mmol) in dichloromethane (10 ml) was added triethylamine (35 mg, 0.35 mmol), 4-methylbenzene-1-sulfonyl chloride (79 mg, 0.41 mmol ) and 4-dimethylaminopyridine (5 mg, 0.04 mmol). The resulting solution was stirred at room temperature overnight. The reaction was then quenched with water (30 ml). The resulting solution was extracted with dichloromethane (20 ml × 3). The organic phase was washed with brine (20 ml × 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1: 3) as eluent to give the title product (0.17 g, 84% yield).

[00200] Step 5. Synthesis of 17A and 17B

[00201] To a solution of 17-5 (170 mg, 0.29 mmol) in acetonitrile (10 ml) were added 3- (fluoromethyl) azetidine (103 mg, 1.16 mmol) and cesium carbonate (376 mg, 1.14 mmol ). The resulting solution was stirred at 80 ° C overnight. After cooling, the mixture was diluted with ice water (30 ml) and was extracted with ethyl acetate (30 ml × 3). The organic phase was washed with brine (20 ml × 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash preparative HPLC [Column: C 18; Mobile phase: CH ₃ CN / H ₂ O (0.05% NH ₄ HCO ₃ ); Gradient: 70% -86% MeCN, 8 min; Detector: 254 nm] to give racemate 17 (30 mg, 21% yield) as a white solid.

[00202] Racemate 17 was isolated by chiral preparative HPLC (Column: AD-H; Mobile phase: Hex / EtOH; Gradient: 13% EtOH, 18 min; Rate: 20 ml / min; Detector: 254 nm] to obtain the target products.

[00203] Compound 17A: Chiral HPLC [Column: AD, 100 mm, 4.6 mm, 0.6 ml / min, mobile phase: hexane (0.1% TFA) / ethanol; Gradient: 15% EtOH; Detector: 254 nm], retention time = 3.03 min. LCMS (ES, m / z) 505.4 [M + H] ⁺ ; ¹ NMR (300 MHz, CD ₃ OD, ppm): δ 7.49-7.46 (m, 1 H), 7.32-7.29 (m, 1 H), 7.21-7.18 ( m, 2 H) 6.54 (d, J = 10.8 Hz, 2 H), 5.14 (s, 1 H), 4.55 (d, J = 5.7 Hz, 1 H), 4 , 40 (d, J = 5.4 Hz, 1 H), 4.01-3.98 (m, 2 H), 3.90 (d, J = 5.4 Hz, 1 H), 3.69-3 , 51 (m, 2 H), 3.32-3.19 (m, 2 H), 2.97-2.86 (m, 5 H), 2.86-2.57 (m, 1 H) , 2.53-2.38 (m, 1H), 1.28-1.10 (m, 9H).

[00204] Compound 17B: Chiral HPLC [Column: AD, 100 mm, 4.6 mm, 0.6 ml / min, mobile phase: hexane (0.1% TFA) / ethanol; Gradient: 15% EtOH; Detector: 254 nm], retention time = 5.20 min. LCMS (ES, m / z) 505.4 [M + H] ⁺ ; ¹ NMR (300 MHz, CD ₃ OD, ppm): δ 7.47 (s, 1 H, 7.30-7.19 (m, 3 H), 6.54 (d, J = 11.1 Hz, 2 H), 5.14 (s, 1 H), 4.55 (d, J = 5.1 Hz, 1 H), 4.40 (d, J = 4.8 Hz, 1 H), 4, 06 (s, 2 H), 3.68 (s, 1 H), 3.56-3.51 (m, 2 H), 3.31-3.20 (m, 2 H), 3.07- 2.88 (m, 5 H), 2.67-2.33 (m, 2 H), 1.63-1.40 (m, 9 H).

[00205] Similarly, the following additional compounds were prepared in accordance with the invention.

[00206] Example 5: Synthesis of Compound 20

[00207] Stage 1. Synthesis 20-1

[00208] To a solution of 4-bromo-2-chloro-6-fluorobenzaldehyde (1.0 g, 4.21 mmol) in N, N-dimethylformamide (30 ml) was added triethylamine (840 mg, 8.30 mmol), acetate palladium (47 mg, 0.21 mmol), P (o-tol) ₃ (130 mg, 0.43 mmol) and ethylprop-2-enoate (630 mg, 6.29 mmol). The reaction mixture was then purged with nitrogen three times and stirred at 100 ° C overnight. After cooling to room temperature, the reaction mixture was quenched by the addition of ice water. The mixture was extracted with dichloromethane (50 ml × 3). The organic phase was washed with brine (30 ml × 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1: 5) as eluent to give the title product (0.8 g, 74% yield).

[00209] Stage 2. Synthesis 20-2

[00210] To a solution of (2R) -1- (1H-indol-3-yl) propan-2-amine (340 mg, 1.95 mmol) in toluene (10 ml) was added ethyl (2E) -3- (3 -chloro-5-fluoro-4-formylphenyl) prop-2-enoate (600 mg, 2.34 mmol) and acetic acid (230 mg, 3.83 mmol). The reaction mixture was stirred at 80 ° C overnight, then cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (2: 5) to give the title product (0.7 g, 87% yield).

[00211] Stage 3. Synthesis 20-3

[00212] To a solution of ethyl 20-2 (700 mg, 1.70 mmol) in 1,4-dioxane (20 ml) were added N, N-diisopropylethylamine (1.09 g, 8.43 mmol) and 2-fluoro- 2-methylpropyl trifluoromethanesulfonate (1.14 g, 5.09 mmol). The reaction mixture was stirred at 120 ° C overnight, then cooled to room temperature and concentrated in vacuo. The residue was purified by flash preparative HPLC [Column: SunFire Prep C 18, 5 um, 19 * 150 mm; Mobile phase: MeCN / Water (0.1% FA); Gradient: 71% - 86% MeCN, 6 min, 25 ml / min; Detector: 220 nm] to obtain the target product (0.25 g, yield 30%).

[00213] Stage 4. Synthesis 20

[00214] To a solution of ethyl 20-3 (250 mg, 0.51 mmol) in tetrahydrofuran (30 ml) and water (3 ml) was added lithium hydroxide (25 mg, 1.04 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The pH of the residue was adjusted to 5-6 with hydrogen chloride (1N). The mixture was extracted with dichloromethane (30 ml × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in MeCN / H ₂ O and dried by lyophilization to obtain the target product (75.4 mg, 32% yield). LCMS (ES, m / z) 459.16 [M + H] ⁺ ; ¹ NMR: (300 MHz, DMSO-d ₆ , ppm): δ 12.55 (br s, 1 H), 10.44 (s, 1 H), 7.70 (s, 1 H), 7.59 -7.52 (m, 2H), 7.41 (d, J = 7.2 Hz, 1 H), 7.17 (d, J = 6.9 Hz, 1 H), 7.01-6, 92 (m, 2 H), 6.69 (d, 7 = 15.9 Hz, 1 H), 5.35 (s, 1 H), 3.68-3.61 (m, 1 H), 3 , 08-2.90 (m, 2 H), 2.64-2.59 (m, 1 H), 2.50-2.20 (m, 1 H), 1.16-1.05 (m, 9 H).

[00215] Example 6: Synthesis of Compound 21

[00216] Stage 1. Synthesis 21-1

[00217] To a solution of (2R) -1- (1H-indol-3-yl) propan-2-amine (700 mg, 4.02 mmol) and 2-fluoro-2-methylpropyltrifluoromethanesulfonate (1.082 g, 4.80 mmol ) in 1,4-dioxane (10 ml) was added N, N-diisopropylethylamine (1.56 g, 12.06 mmol). The resulting solution was stirred at 70 ° C overnight. After cooling to room temperature, the mixture was diluted with water (50 ml) and extracted with ethyl acetate (100 ml × 2). The organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product (830 mg, 83% yield).

[00218] Stage 2. Synthesis 21-2

[00219] A solution of 21-1 (830 mg, 3.34 mmol), 4-bromo-2,6-dichlorobenzaldehyde (710 mg, 2.80 mmol) and acetic acid (350 mg, 5.83 mmol) in toluene ( 10 ml) was stirred at 80 ° C overnight. The mixture was then cooled to room temperature, diluted with water (50 ml) and extracted with ethyl acetate (100 ml × 2). The organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product (1 g, 74% yield).

[00220] Stage 3. Synthesis 21-3

[00221] Solution 21-2 (100 mg, 0.21 mmol), ethylprop-2-enoate (31 mg, 0.31 mmol), Pd (OAc) ₂ (95 mg, 0.42 mmol), Ph ₃ P (110 mg) and triethylamine (42 mg, 0.42 mmol) in N, N-dimethylformamide (5 ml) was stirred at 100 ° C for 48 h. After cooling to room temperature, the mixture was diluted with water (50 ml) and extracted with ethyl acetate (100 ml × 2). The organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in DMF and purified by preparative HPLC under the following conditions [Column: X Bridge Shield RP18 OBD, 5 μm, 19 x 150 mm; Mobile phase A: Water (0.05% MH ₄ HCO ₃ ), Mobile phase B: MeCN; Gradient: 25% MeCN to 54% in 8 min; Detector: UV 254 nm] to obtain the target product (76 mg, 73% yield).

[00222] Stage 4. Synthesis 21

[00223] To a solution of 21-3 (76 mg, 0.15 mmol) in tetrahydrofuran (5 ml) and water (1 ml) was added lithium hydroxide (13 mg, 0.31 mmol). The resulting solution was stirred at 25 ° C for 15 hours. The mixture was then diluted with water (20 ml). The pH of the residue was adjusted to 6 with hydrogen chloride (1N) and extracted with ethyl acetate (50 ml × 2). The organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was diluted with acetonitrile / water and dried by lyophilization to give the title product (15.6 mg, 22% yield). LCMS (ES, m / z): 476.38 [M + H] ⁺ . ¹ NMR (300 MHz, CD ₃ OD-d ₄ , ppm): δ 7.66 (s, 1H), 7.44-7.34 (m, 3H), 7.17 (dd, J = 1.8 , 6.6 Hz, 1H), 7.00-6.92 (m, 2H), 6.54 (d, J = 15.9 Hz, 1H), 5.71 (s, 1H), 3.87 -3.83 (m, 1H), 3.22-3.19 (m, 1H), 3.16-2.97 (m, 1H), 2.68-2.64 (m, 1H), 2 , 37-2.22 (m, 1H), 1.14-1.11 (m, 6H), 1.09 (d, J = 10.2Hz, 3H).

[00224] Example 7: Synthesis of Compound 22

[00225] Stage 1. Synthesis 22-2

[00226] To a solution of 6-methoxy-1H-indole-3-carbaldehyde (2 g, 11.42 mmol) in toluene (20 ml) were added acetic acid (4.4 g, 57.08 mmol) and nitroethane (10 ml ). The resulting solution was stirred at 130 ° C for 6 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The resulting solution was diluted with ethyl acetate (100 ml). The mixture was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product (2.5 g, crude).

[00227] Stage 2. Synthesis 22-3

[00228] To a solution of 22-2 (2.5 g, 10.76 mmol) in tetrahydrofuran (100 ml) was added lithium aluminum hydride (1.63 g, 42.95 mmol) in portions at 0 ° C. The resulting solution was then stirred at 65 ° C for 4 hours. After cooling to room temperature, the reaction was quenched by the addition of ice water (100 ml) and extracted with ethyl acetate (100 ml × 3). The organic phase was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product (1.5 g, crude).

[00229] Stage 3. Synthesis 22-4

[00230] A mixture of 1- (6-methoxy-1H-indol-3-yl) propan-2-amine (1.5 g, 7.34 mmol), 2-fluoro-2-methylpropyl trifluoromethanesulfonate (1.8 g, 8 , 03 mmol) and N, N-diisopropylethylamine (1.05 g, 8.08 mmol) in dioxane (20 ml) was stirred at 70 ° C for 12 h. After cooling to room temperature, the mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 3). The organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1 / 10-1 / 1) to give the title product (1 g, 49% yield).

[00231] Step 4. Synthesis of 22-6A and 22-6B

[00232] A mixture of (2-fluoro-2-methylpropyl) [1- (6-methoxy-1H-indol-3-yl) propan-2-yl] amine (1 g, 3.59 mmol), ethyl (2E) -3- (3,5-difluoro-4-formylphenyl) prop-2-enoate (860 mg, 3.58 mmol) and acetic acid (1 ml) in toluene (10 ml) was stirred at 80 ° С for 12 h After cooling to room temperature, the mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml × 3). The organic phase was concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1 / 100-1 / 10) to give the title product as a racemate (750 mg). The racemate was separated by chiral preparative HPLC [Column, IA; Mobile phase: hexane: EtOH = 80: 20, 20 ml / min; Detector: UV = 254 nm] to give 22-6A (RT = 4.45 min) as a white solid and 22-6 B (RT = 9.27 min) as a white solid.

[00233] Step 5. Synthesis of 22A and 22B

[00234] To a solution of 22-6A (30 mg, 0.06 mmol) in tetrahydrofuran (2 ml) and water (0.5 ml) was added lithium hydroxide (4.32 mg, 0.18 mmol). The resulting mixture was stirred at room temperature for 12 hours, then diluted with water (5 ml). The pH of the solution was adjusted to 6 with hydrogen chloride (1N) and extracted with ethyl acetate (5 ml × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title product 22A (12.5 mg, 44% yield). LCMS (ES, m / z): 473.2 [M + H] ⁺ . ¹ NMR (300 MHz, CD ₃ OD, ppm): δ 7.57 (d, J = 16.2 Hz, 1H), 7.29 (m, 3H), 6.75 (d, J = 2.4 Hz, 1H), 6.65 (dd, J = 2.1, 8.4 Hz, 1H), 6.54 (d, J = 15.9 Hz, 1H), 5.31 (s, 1H), 3.76 (s, 3H), 3.69-3.67 (m, 1H), 3.05-2.98 (m, 2H), 2.62-2.38 (m, 2H), 1, 20-1.1 l (m, 9H).

[00235] In a similar manner, hydrolysis of 22-6B was performed to give 22 V. LCMS (ES, m / z): 473.2 [M + H] ⁺ . ¹ NMR (300 MHz, CD ₃ OD, ppm): δ 7.57 (d, J = 16.2 Hz, 1H), 7.29-7.18 (m, 3H), 6.75 (d, J = 2.4 Hz, 1H), 6.65 (dd, J = 2.1, 8.4 Hz, 1H), 6.54 (d, J = 15.9 Hz, 1H), 5.31 (s , 1H), 3.76 (s, 3H), 3.69-3.67 (m, 1H), 3.05-2.98 (m, 2H), 2.62-2.38 (m, 2H ), 1.20-1.11 (m, 9H).

[00236] Example 8: Synthesis of Compound 23

[00237] Stage 1. Synthesis 23-2

[00238] To a solution of 5- (benzyloxy) -1H-indole-3-carbaldehyde (2 g, 7.96 mmol) in toluene (20 ml) were added nitroethane (24 ml) and ammonium acetate (600 mg, 8.00 mmol ). The mixture was then stirred at 130 ° C. for 4 hours. After cooling to room temperature, the mixture was diluted with water (100 ml) and extracted with ethyl acetate (50 ml x 3). The organic phase was washed with brine (50 ml × 2), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product (2.45 g, crude).

[00239] Stage 2. Synthesis 23-3

[00240] To a solution of lithium aluminum hydride (1.2 g, 31.62 mmol) in tetrahydrofuran (30 ml) was added 5- (benzyloxy) -3 - [(1Z) -2-nitroprop-1-en-1-yl ] -1H-indole (2.45 g, 7.95 mmol) in tetrahydrofuran (20 ml). The mixture was stirred at 0 ° C for 30 min and then at 65 ° C for 5 h. After cooling to room temperature, the mixture was diluted with ice water (100 ml) and extracted with ethyl acetate (100 ml × 3). The organic phase was washed with brine (100 ml × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title product (2.2 g, crude).

[00241] Stage 3. Synthesis 23-4

[00242] To a solution of 1- [5- (benzyloxy) -1H-indol-3-yl] propan-2-amine (1.2 g, 4.28 mmol) in 1,4-dioxane (30 ml) was added 2 -fluoro-2-methylpropyl trifluoromethanesulfonate (960 mg, 4.28 mmol) and N, N-diisopropylethylamine (770 mg). The mixture was then stirred at 70 ° C overnight. After cooling to room temperature, the mixture was diluted with water (100 ml) and extracted with ethyl acetate (50 ml × 3). The organic phase was washed with brine (50 ml × 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (2/3) as eluent to give the title product (430 g, 28% yield).

[00243] Stage 4. Synthesis 23-5

[00244] To a solution of [1- [5- (benzyloxy) -1H-indol-3-yl] propan-2-yl] (2-fluoro-2-methylpropyl) amine (430 mg, 1.21 mmol) in methanol (20 ml) was added palladium-carbon (100 mg). The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere (1 atm). The mixture was filtered through celite, the filtrate was concentrated in vacuo to obtain the target product (280 mg, 87% yield).

[00245] Stage 5. Synthesis 23-6

[00246] To a solution of 3- [2 - [(2-fluoro-2-methylpropyl) amino] propyl] -1H-indole-5-ol (280 mg, 1.06 mmol) in toluene (30 ml) was added ethyl ( 2E) -3- (3,5-difluoro-4-formylphenyl) prop-2-enoate (250 mg, 1.04 mmol) and acetic acid (200 mg, 3.33 mmol). The mixture was then stirred at 80 ° C overnight. After cooling to room temperature, the mixture was diluted with water (100 ml) and extracted with ethyl acetate (50 ml × 3). The organic phase was washed with brine (50 ml × 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1: 3) as eluent to give the title product (180 g, 36% yield).

[00247] Stage 6. Synthesis 23

[00248] To a solution of 23-6 (100 mg, 0.21 mmol) in tetrahydrofuran (5 ml) and water (1 ml) was added lithium hydroxide (10 mg, 0.42 mmol). The mixture was then stirred at room temperature overnight and then diluted with water (20 ml). The pH of the solution was adjusted to 6 with hydrogen chloride (1N) and extracted with ethyl acetate (20 ml × 3). The organic phase was washed with brine (20 ml × 2), dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title product (11.9 mg, 13% yield). LCMS (ES, m / z) 459.18 [M + H] ⁺ ; ¹ HNMR: (300 MHz, CD ₃ OD, ppm): δ 7.53 (d, J = 16.2 Hz, 1H), 7.18 (d, J = 9.9 Hz, 2H), 6.99 (d, J = 8.7 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 6.59-6.50 (m, 2H), 5.26 (s, 1H) , 3.69-3.63 (m, 1H), 3.08-2.87 (m, 2H), 2.56-2.50 (m, 1H), 2.46-2.32 (m, 1H), 1.32-1.09 (m, 9H).

[00249] Example 9: Synthesis of Compound 24 and Its Derivatives

[00250] Stage 1. Synthesis 24-1

[00251] To a solution of 1-fluorocyclopropane-1-carboxylic acid (700 mg, 6.73 mmol) in N, N-dimethylformamide (10 ml) was added N, N-diisopropylethylamine (1.5 g, 11.61 mmol), HATU (2.4 g, 6.32 mmol) and (2R) -1- (1H-indol-3-yl) propan-2-amine (1 g, 5.74 mmol). After stirring at room temperature overnight, the mixture was quenched by the addition of ice water (20 ml). The mixture was extracted with ethyl acetate (20 ml × 3). The organic phase was washed with brine (20 ml × 3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1: 3) as eluent to give the title product (600 mg, 40% yield).

[00252] Stage 2. Synthesis 24-2

[00253] A solution of 24-1 (600 mg, 2.30 mmol) in BH ₃ .THF (1 M) (20 ml) was heated under reflux overnight. After cooling to room temperature, the mixture was concentrated in vacuo, the residue was dissolved in methanol (20 ml), then heated under reflux overnight. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with water (100 ml) and was extracted with ethyl acetate (100 ml × 3). The organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude mixture was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1: 2) as eluent to give the title product (350 mg, 62% yield).

[00254] Step 3. Synthesis 24-3

[00255] To a solution of (R) -N - ((1-fluorocyclopropyl) methyl) -1- (1H-indol-3-yl) propan-2-amine (350 mg, 1.42 mmol) and ethyl (2E) -3- (3,5-difluoro-4-formylphenyl) prop-2-enoate (341.5 mg, 1.42 mmol) in toluene (5 ml), acetic acid (1 drop) was added. After stirring at 80 ° C for 2 h, the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1: 2) as eluent to give the title product (120 mg, 18% yield).

[00256] Stage 4. Synthesis 24

[00257] To a solution of 24-3 (120 mg, 0.26 mmol) in tetrahydrofuran (0.9 ml) and water (0.1 ml) was added lithium hydroxide (12.3 mg, 0.51 mmol). The resulting solution was stirred at room temperature overnight. The pH of the solution was adjusted to 6 with hydrogen chloride (1N) and the mixture was extracted with ethyl acetate (20 ml × 3). The organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1: 1) as eluent to give the title product (49.9 mg, 44% yield). LCMS (ES, m / z) 441.30 [M + H] ⁺ ; ¹ HNMR: (300 MHz, DMSO-d ₆ , ppm): δ 12.50 (br s, 1H), 10.59 (s, 1H), 7.56-7.40 (m, 4H), 7, 19 (d, J = 5.7 Hz, 1H), 700-7.6.95 (m, 2H), 6.67 (d, J = 12 Hz, 1H), 5.23 (s, 1H), 3, 58-3.56 (m, 1H), 3.09-2.88 (m, 2H), 2.67-2.63 (m, 2H), 1.07 (d, J = 5.1 Hz, 3H) 0.94-0.89 (m, 2H), 0.56-0.51 (m, 2H).

[00258] Similarly, the following additional compounds were prepared in accordance with the invention.

[00259] Biological Analysis of Examples of Compounds Described herein

[00260] Example 9. Analysis of the degradation of ER MCF-7

[00261] The level of ER degradation due to the SRED, described in this patent, was analyzed by the method of multivariable cell analysis. Briefly, MCF-7 cells from ER-positive human breast cancer were seeded in 96-well Grenier plates at 5000 cells per well and grown in RPMI 1640 supplemented with 10% FBS (Gibco) at 37 ° C with 5% CO ₂ within 48 hours. Then, 1 μl of a complex solution (in DMSO) was added to the cells to obtain a final concentration of 1 nM per well of the treated cells. DMSO with the same final concentration (%) per well was used for negative control on each plate. After 4 hours or 24 hours of treatment at 37 ° C with 5% CO ₂ cells were fixed and permeable. The medium from each well was removed, the cells were gently washed with 1X PBS for 5 minutes, the washing procedure was repeated 3 times. The cells were then fixed with 4% formaldehyde freshly prepared in 1X PBS at room temperature for 20 minutes, then gently washed with 1X PBS 3 times for 5 minutes each time. The assay plate was incubated with 200 μl of 1XPBS containing 0.2% Triton-X100 for 5 minutes at room temperature, then the cells were washed again with 1XPBS 3 times for 5 minutes each time. The cells were then incubated with blocking buffer (1X PBS with 5% BSA) at room temperature for 1 hour. For immunostaining, the blocking buffer was removed, and a primary anti-ER antibody (ER1D5, Santa Cruz) diluted in blocking buffer (1: 400) was added to each well, the cells were incubated overnight at 4 ° C. The next day, cells were washed with 1X PBS 3 times for 5 minutes each time. Fluorochrome-labeled secondary antibody (goat anti-mouse IgG, Alexa Fluor 488 conjugate, ThermoFisher, Cat #: A-11001) diluted in 1% BSA in 1X PBS (1: 1000) was added to each well and incubated with cells for 45 minutes at 37 ° C in a humid environment in the dark. The cells were washed with 1X PBS 3 times for 5 minutes each time. The cells were incubated with DAPI (Beyotime, 1 μg / ml) for 10 minutes and washed with 1X PBS 3 times for 5 minutes each time. For multivariable analysis, plate data was read on a Cellomics ArrayScan ™ XTI High Content Platform (ASN00002P) with excitation at 485 nm, imaging data was collected at a minimum of 1000 cells per well. SRED-induced ER degradation in MCF-7 cells was measured using a negative control DMSO as the primary method.

[00262]

[00263]

[00264] Example 10. Study of MCF-7 Cell Growth

[00265] The activity of the compound was assessed using the CellTiter-Glo luminescence cell viability assay (Promega # G7572) in the MCF-7 breast cancer cell line. Cells grown in log phase were trypsinized, seeded in a 96-well cell culture plate at a density of 2 × 10 ³ per well, and incubated overnight at 37 ° C. with 5% CO ₂ in a humidified culture chamber. The next day, compounds were prepared in 100% DMSO, serially diluted and added to cells at the following final concentrations: 316, 100, 31.6, 10, 3.16, 1, 0.32, 0.1, 0.03, 0 , 01, 0.003 and 0.001 nM. For control, a control solution of DMSO vehicle of the same volume and concentration was added to the control wells in each plate. The cells were incubated with compounds in a culture chamber at 37 ° C for 6 days. Celltiter-glo kit from Promega was used to determine cell viability according to the manufacturer's instructions. Briefly, 50 μl of Celltiter-glo reagent was added to each well, the plate (covered with aluminum foil) was gently rocked for 10 minutes to induce cell lysis at room temperature. Luminescence was measured using a SPECTRAmax i3 reader. Cell growth inhibition IC _{50 was} calculated using GraphPad Prism V5.0 software. % inhibition = (1- (maximum signal / minimum signal)) * 100%.

[00266]

[00267] Example 11. Study of clearance of human hepatocytes

[00268] The in vitro hepatocyte clearance of the compound described herein was studied using pooled human hepatocytes obtained from Bioreclamation IVT (Westbury, NY, Cat # X008001, Lot # TQJ). The analysis was performed according to the manufacturer's instructions. Briefly, 10 mM stock solution of test compound and positive control (Verapamil) was prepared in 100% DMSO. Thawing medium (50 ml) used in the study contained: 31 ml Williams E medium (GIBCO Cat # 12551-032); 15 ml isotonic percoll (GE Healthcare Cat # 17-0891-09); 500 μl 100XGlutaMax (GIBCO Cat # 35050); 750 μl HEPES (GIBCO Cat # 15630-080); 2.5 ml FBS (Corning Cat # 35-076-CVR); 50 μl human insulin (GIBCO Cat # 12585-014) and 5 μl dexamethasone (NICPBP). The incubation medium was obtained from Williams E medium supplemented with 1xGlutaMax. The thawing medium and additional incubation medium (without serum) were placed in a water bath at 37 ° C for at least 15 minutes before use. Compound stock solutions were diluted to 100 μM by combining 198 μl of 50% acetonitrile / 50% water and 2 μl of a 10 mM stock solution. Verapamil was used as a positive control in the assay. The vials with cryopreserved hepatocytes were removed from storage and thawed in a water bath at 37 ° C with gentle shaking. The contents of the vial were poured into a 50 ml conical thaw tube. The vials were centrifuged at 100 g for 10 minutes at room temperature. The thawed medium was removed and the hepatocytes were resuspended in serum-free incubation medium to obtain approximately 1.5 x 10 ⁶ cells / ml. The viability and density of hepatocytes were calculated by trypan blue exclusion, then the cells were diluted with an incubation medium without serum to a density of viable cells of 0.5 × 10 ⁶ viable cells / ml. Then, a part of hepatocytes at 0.5 × 10 ⁶ viable cells / ml was boiled for 5 minutes before adding to the plate as a negative control to eliminate enzymatic activity, so that little or no renewal of the substrate was observed. After boiling, hepatocytes were used to prepare negative samples. Aliquots of 198 μl hepatocytes were dispensed into each well of an uncoated 96 well plate. The plate was placed in an incubator on an orbital shaker at 500 rpm for about 10 minutes. Aliquots of 2 μl of 100 μM test compound or positive control were added to the appropriate wells of an uncoated 96 well plate to initiate the reaction. Two parallel analyzes were performed. The plate was incubated in an incubator on an orbital shaker at 500 rpm for a specified time. 25 μl of the contents were transferred and mixed with 6 volumes (150 μl) of cold acetonitrile with IS (200 nM imipramine, 200 nM labetalol and 200 nM diclofenac) to terminate the reaction at times of 0, 15, 30, 60, 90 and 120 minutes. Samples were centrifuged at 3220 g for 25 minutes, and 150 μl aliquots of supernatants were used for LC-MS / MS analysis. All calculations for data analysis were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The in vitro half-life (t _1/2 ) of the parent compound was determined by regression analysis of the curve of the percentage of disappearance of the parent compound over time. The in vitro half-life (in vitro t _1/2 ) was determined by the slope value: in vitro t _1/2 = 0.693 / k. In vitro conversion t _1/2 (in min) to scaled unbound drug intrinsic clearance (scaled unbound drug CL _int , in ml / min / kg) was performed using the following equation (mean of repeated determinations): scaled unbound drug _int CL = kV / N × scaling factor, where V = incubation volume (0.5 ml); N = number of hepatocytes per well (0.25 x 10 ⁶ cells). Scale factors for predicting in vivo internal clearance using human hepatocytes are given below: liver weight (g liver / kg body weight): 25.7; concentration of hepatocytes (10 ⁶ cells / g liver): 99; scaling ratio: 2544.3.

[00269] Example 12. PK study in mice

[00270] PK study in mice PK (intravenous 3 mg / kg body weight and orally 30 mg / kg body weight) was performed using male CD1 mice (25-33 g) obtained from SLAC Laboratory Animal Co., LTD, Shanghai) ... A compound of the following composition was prepared: 5% DMSO, 5% Solutol HS 15 and 9% HPBCD in water. For an intravenous (iv) dose of 3 mg / kg body weight and an oral (po) dose of 30 mg / kg body weight, the concentration of the compound was 0.2 mg / ml and 1 mg / ml, respectively. The compound was prepared in the morning immediately prior to dosing. Oral administration was carried out using an oral gastric tube in a volume of 10 ml / kg, and intravenous administration through the tail vein in a volume of 5 ml / kg. Three mice were used for each route of administration of each compound at each dose. Consecutive blood samples (30 μL of whole blood at each time point) were collected into K2 EDTA tubes via the facial vein at the following time points: 5 minutes (IV only), 30 minutes, 1, 2, 4, 6, 8, 12 and 24 hours. For each blood sample collected, a 20 μl blood sample was immediately taken and mixed thoroughly with 60 μl water in a 96-well plate (whole blood: water = 1: 3 v / v). The diluted blood samples were stored in a -80 ° C freezer prior to analysis. For analysis, an aliquot of 20 μL of sample with 200 μL IS (Glipizide, 100 ng / ml) in ACN was added. The mixture was vortexed for 2 minutes and centrifuged at 5800 rpm for 10 minutes. An aliquot of 2 μl of the supernatant was injected for LC-MS / MS analysis. For the calibration curve, compound was used in an amount of 2.0-3000 ng / ml in diluted blood of a CD1 mouse. The obtained pharmacokinetic data are shown in the following table:

[00271] Example 13. Study of the effectiveness of treatment of xenograft human breast cancer xMCF-7 in mice

[00272] To investigate the in vivo efficacy of the SRED compounds described herein, female nude mice were inoculated with ER-positive human breast cancer xMCF-7 cells. XMCF-7 cells were obtained from MCF-7 tumor (ATCC) grown in nude mice. Briefly, female balb / c mice (6-7 weeks old) were first inoculated subcutaneously in the back with estrogen tablets (0.5 mg, 60 days release, from Innovative Research of America, Cat # SE-121). Two days later, each mouse was inoculated with 5,000,000 xMCF-7 cells obtained as 0.2 ml of cell suspension in a 1: 1 mixture of MEM from Eagle for growing culture medium and Matrigel (Corning Cat # 354234) for each injection. After the tumor size reached approximately 235 mm ³ , the xMCF-7 tumor xenograft mice were randomized into groups of 10 mice and drug therapy was initiated. Each compound was prepared in a dosing vehicle (5% DMSO, 5% Solutol HS15 and 10% HPBCD in water) and administered orally at 5 mg / kg or 30 mg / kg once daily for 28 days, except that fulvestrant was prepared in peanut oil and administered at 250 mg / kg subcutaneously once a day for 28 days. In this study, almost complete inhibition of tumor growth was observed as a result of drug therapy, with compound 25 being more effective in vivo than fulvestrant, GDC-0810 and AZD9496 (Figure 1).

[00273] In another study, xMCF-7 treatment was started when the tumor reached about 250 mm ³ . Each drug was administered at 2 mg / kg orally once a day for 28 days. Significant inhibition of tumor growth and tumor regression was found, compounds 12, 21 and 25 were more effective than AZD9496 (Figure 2).

[00274] Example 14: The combination of the compound SIER 25 with the CDK4 / 6 inhibitor palbociclib in the xMCF-7 xenograft model.

[00275] A CDK4 / 6 inhibitor such as palbociclib is approved for ER-positive, Her2-negative metastatic breast cancer. To investigate the possibility of combining SRIER and a CDK4 inhibitor to further enhance the efficacy of treatment for ER-positive breast cancer, Compound 25 SIER was tested in combination with the CDK4 / 6 inhibitor palbociclib in the xMCF-7 human breast cancer xenograft model. In this study, when the xMCF-7 tumor reached approximately 250 mm ³ , compound 25 was administered orally once a day for 28 days, palbociclib was administered orally at 50 mg / kg, once a day for 14 days. As shown in Figure 3, the combination of palbociclib and compound 25 provides better tumor growth regression than palbociclib or compound 25 when used alone.

Equivalents and scope of the invention

[00276] In the claims, the singular forms, the singular, may mean one or more of one, unless otherwise indicated or unless the context clearly indicates otherwise. Claims or descriptions that include “or” between one or more group members are deemed complete if one, more than one, or all group members are present, used, or otherwise refer to the product or process, unless otherwise stated or otherwise follows from the context. The invention includes embodiments in which exactly one group element is present, used, or otherwise related to a given product or process. The invention includes embodiments in which more than one or all of the group members are present, used, or otherwise related to a given product or process.

[00277] In addition, the invention encompasses all variations, combinations and transformations in which one or more of the restrictions, elements, claims, descriptive terms in one or more claims are presented in another claim. For example, any claim dependent on another claim may be amended to include one or more of the limitations contained in any other claim dependent on the same main claim. If the elements are present in the form of an enumeration, for example, in the format of a Markush group, then each subgroup of elements is considered also open, and any element (s) can be removed from the group. It should be understood that, in general, if the invention or aspects of the invention are stated to include specific elements and / or features, then certain embodiments of the invention or aspects of the invention consist of or essentially consist of such elements and / or features. For simplicity's sake, such implementations are not specifically presented in the same terms herein. It should also be borne in mind that the terms "including" and "comprising" are intended to be open and are open to the inclusion of additional elements or steps. Ranges shown include limit values. In addition, unless otherwise indicated, or unless otherwise required from the context and understood by those skilled in the art, values presented as ranges may imply any particular value or sub-range within the indicated ranges in other embodiments of the invention up to a tenth of a unit of the lower limit range unless the context clearly indicates otherwise.

[00278] Throughout this application, references are made to various issued patents, published patent applications, journal articles, and other publications, each of which is incorporated herein by reference. In the event of a conflict between any incorporated references and the present specification, the specification shall prevail. In addition, any specific prior art embodiment of the present invention may be explicitly excluded from any one or more of the claims. Such embodiments are considered to be known to those skilled in the art, so they can be excluded, even if the exclusion is not explicitly expressed in the present description. Any particular embodiment of the present invention may be excluded from any claim for any reason, regardless of whether it relates to the prior art.

[00279] Many equivalents to the specific embodiments described herein are understood by those skilled in the art, or may be determined by no more than routine experimentation. It is intended that the scope of the embodiments of the present invention described herein is not limited by the above description, but rather is consistent with the description in the appended claims. It will be understood by those skilled in the art that various changes and modifications to this disclosure may be made without departing from the spirit or scope of the present invention as defined in the following claims.

Claims (55)

1. Compound of formula ( I )

( I ) or a pharmaceutically acceptable salt of said compound, Where: A represents –CH = or –N = depending on the valency; W is –NH– or –O–; a is 1; n is 1, 2, 3, or 4; each R ^{1 is} independently hydrogen, F, Cl, unsubstituted C _1-6 alkyl, —CF ₃ , —OR ^A, or —CN; R ² is hydrogen, unsubstituted C _1-6 alkyl, or CF ₃ ; R ³ is hydrogen, halogen, or unsubstituted C _1-6 alkyl; R ⁴ is hydrogen, halogen, or unsubstituted C _1-6 alkyl; R ⁵ is chlorine; R ⁶ is fluorine or chlorine; R ⁷ represents —CH ₂ F; R ^A is hydrogen or unsubstituted C _1-6 alkyl. 2. A compound according to claim 1, wherein the compound is a compound of formula (IA)

(IA) or a pharmaceutically acceptable salt of said compound, wherein A, W, a, n, R ¹ -R ⁷ and R ^A are as defined in claim 1. 3. A compound according to any one of claims 1, 2, characterized in that the compound is a compound of the formula

,

,

,

,

,

or a pharmaceutically acceptable salt of said compound. 4. Compound of formula (II)

( Ii ) or a pharmaceutically acceptable salt of said compound, Where: A represents –CH = or –N = depending on the valency; W is –NH–, –O–, or –S–; a is 1; each R ^{1 is} independently hydrogen, F, Cl, —CF ₃ , unsubstituted C _1-6 alkyl, —OR ^A, or —CN; R ² is hydrogen, unsubstituted C _1-6 alkyl, or —CF ₃ ; R ³ is hydrogen, F or unsubstituted C _1-6 alkyl; R ⁴ is hydrogen, F or unsubstituted C _1-6 alkyl, or R ³ and R ⁴ taken together with intermediate atoms form unsubstituted cyclopropyl; R ⁸ is hydrogen, halogen or methyl; R ^A1 is unsubstituted C _1-6 alkyl, chloro or fluoro; R ^A2 is unsubstituted C _1-6 alkyl, chlorine or fluoro, wherein: (i) R ^A1 or R ^A2 is chlorine or (ii) both R ^A1 and R ^A2 are chlorine; R ^A is hydrogen or unsubstituted C _1-6 alkyl. 5. A compound according to claim 4, wherein the compound is a compound of formula (IIA)

(IIA) or a pharmaceutically acceptable salt of said compound, wherein A, W, a, R ¹ -R ⁴ , R ⁸ , R ^A1 , R ^A2 and R ^A are as defined in claim 4. 6. A compound according to claim 4 or 5, or a pharmaceutically acceptable salt of said compound, wherein A is —CH =. 7. A compound according to any one of claims 4-6, or a pharmaceutically acceptable salt of said compound, wherein W is —NH—. 8. A compound according to any one of claims 4 to 7, or a pharmaceutically acceptable salt of said compound, wherein R ¹ is hydrogen. 9. A compound according to any one of claims 4 to 8, or a pharmaceutically acceptable salt of said compound, wherein R ² is unsubstituted C _1-6 alkyl or —CF ₃ . 10. A compound according to claim 9, or a pharmaceutically acceptable salt of said compound, wherein R ² is methyl or ethyl. 11. A compound according to any one of claims 4 to 10, or a pharmaceutically acceptable salt of said compound, wherein at least one of R ³ , R ⁴ , R ^{8 is} independently selected from the group consisting of hydrogen, fluorine and methyl. 12. A compound according to any one of claims 4 to 11, or a pharmaceutically acceptable salt of said compound, wherein at least one of R ^A1 and R ^A2 is chlorine and the other of R ^A1 and R ^A2 is chlorine, F or methyl. 13. A compound according to claim 4, wherein the compound is a compound of the formula

,

,

,

,

,

,

,

,

or a pharmaceutically acceptable salt of said compound. 14. A compound according to any one of claims 4 to 12, or a pharmaceutically acceptable salt of said compound, wherein R ^A1 is chlorine and R ^A2 is chlorine. 15. A pharmaceutical composition having the properties of a selective estrogen receptor (ER) inhibitor, containing an effective amount of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 16. A method of treating a proliferative disease associated with ER activity, comprising administering to a subject in need of treatment an effective amount of a pharmaceutical composition according to claim 15. 17. The method of claim 16, wherein the proliferative disease is ER-activity-related cancer. 18. The method of claim 17, wherein the cancer is ER-positive breast cancer.

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